Cyclic Peptide High-Entropy Noncovalent Glass

Cyclic Peptide High-Entropy Noncovalent Glass | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cyclic Peptide High-Entropy Noncovalent Glass Xuehai Yan, Chengqian Yuan, Wei Fan, Ruirui Xing, Peng Zhou, Shuai Cao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3347593/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Aug, 2024 Read the published version in Nature Nanotechnology → Version 1 posted You are reading this latest preprint version Abstract The design and exploration of stable noncovalent glass based on biomolecules are paramount for the sustainable development of human society. Cyclic peptides (CPs) with remarkable structural rigidity and decent resistance to enzymatic degradation can serve as promising glass formers. However, the potent crystallization tendency hinders their potential in glass construction. Herein, we engineered a series of CP glasses with tunable glass transition behaviors by modulating the conformational complexity of CP clusters. The increasing conformational entropy of the supercooled liquid of CPs compared to their crystalline counterparts is fundamental to the formation of CP noncovalent glass. By incorporating multicomponent CPs, the formation of high-entropy CP (HECP) glass is facilitated, which in turn inhibits the crystallization and decomposition of individual CPs. This process ultimately enhances the stability of CP noncovalent glass. Such HECP glass exhibits enhanced mechanical properties compared to individual CP glass due to the promoted connectivity within the glass network. These findings offer a promising paradigm for designing and developing stable noncovalent glass based on naturally derived biomolecules and advancing their application in pharmaceutical formulations and smart materials. Physical sciences/Chemistry/Supramolecular chemistry/Supramolecular polymers Physical sciences/Materials science/Biomaterials Biological sciences/Biotechnology/Nanobiotechnology Cyclic peptide noncovalent glass high-entropy effect conformation complexity of clusters mechanical property Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Glass is the material that humans shape, and the material that also shapes humans. With its unparalleled versatility and technical capabilities, glass, in its many guises, has fostered numerous cultural and scientific advancements 1 . In the context of sustainability and circular economy, the design and development of next-generation glass should follow the principles that are benign, renewable, and degradable rather than toxic, depleting, and persistent 2 . One such promising avenue is the development of noncovalent biomolecular glasses stabilized by noncovalent interactions between amino acid and peptide derivatives 3 . Such glasses present a striking contrast to traditional inorganic and polymer glasses that rely on strong ionic and covalent interactions Their notable biocompatibility and biodegradability make them an ideal alternative for biodegradable and biorecyclable glasses. When envisioning applications that intersect with biology, such as implantable medical devices or wearable smart devices, it is essential that these noncovalent glasses resist enzymatic hydrolysis throughout their functional lifespan 4 . Moreover, these glasses should also endure the thermal treatments inherent to the device manufacturing processes 5 . Therefore, developing noncovalent glass that can robustly perform in challenging physiological conditions while ensuring minimal rejection is of paramount importance. Cyclic peptides (CPs) feature a cyclic backbone containing two or more amino acids, imparting them with increased stability and resistance to enzymatic degradation compared to their linear counterparts 6–9 . These CPs are ubiquitous in natural organisms such as plants, animals, and microorganisms, especially in marine microorganisms 10 . Furthermore, CPs have demonstrated a wide range of diverse biological and pharmacological activities such as antimicrobial, anticancer, antiviral, immunosuppressive, and anti-inflammatory properties. These activities are attributed to their excellent binding affinity, target selectivity, and low toxicity 11–13 . Therefore, CPs offer a versatile platform for designing and fabricating noncovalent glass for diverse biomedical and other high-tech applications. However, research on CPs has been primarily focused on their long-range ordered self-assemblies, especially in the crystalline state 14–16 . The relatively uncharted territory of the glassy state of CPs can be ascribed to the remarkable structural rigidity of the cyclic scaffold and superior hydrogen-bond-forming ability 17–19 . Despite this, the ongoing quest is to develop an efficient and robust approach to achieve stable CP glass with tailored properties for specific applications. One key hurdle is that the generation of critical crystal nuclei must be effectively inhibited to achieve CP glass. It has been reported that competition between clusters with similar energy levels decreases the probability of selecting viable crystal structures and thereby promotes glass formation 20, 21 . Inspired by this, we postulate that CP glass might be achieved when multiple CP clusters with similar energy coexist. In this work, we have created a series of CP glasses with tunable glass transition temperatures and mechanical properties through modulating the conformational complexity of CP clusters and increasing the conformational entropy. Taking advantage of the significant effect of temperature on CP conformation, we melted the crystalline CPs to disrupt the original long-range intermolecular interactions before observing any thermal decomposition and facilitated the generation of conformational polymorphisms of CP clusters in the supercooled liquid. Upon rapid cooling, these disordered conformers are kinetically preserved, leading to the formation of glass. Further increasing disorder by mixing various CPs makes it possible to achieve a stable high-entropy CP (HECP) glass. Additionally, the concept of HECP glass could be extended to fabricating glass incorporating CPs that are highly crystalline or thermally labile. The increase in conformation entropy, resulting from mixing multiple components, significantly impedes crystallization and prevents the decomposition of individual CPs, ultimately leading to the formation of stable HECP glass. The obtained HECP glass exhibits enhanced mechanical properties compared to individual CP glasses due to the promoted connectivity of the glass network. These findings provide valuable insights into the essential role of entropy in the formation and stabilization of biomolecular glasses. Moreover, these findings broaden the potential applications of biomolecular materials, enabling the development of innovative technologies based on noncovalent glasses that possess enhanced versatility and functionality. Results and discussions The supercooled liquid of CPs is essential for achieving bulk glasses through the melting-quenching method (Fig. 1 a). To avoid the decomposition of CPs during the melting process, we first conducted a series of measurements using thermogravimetric analyzer combined with a differential scanning calorimeter (TGA-DSC) to evaluate the melting point (T m ) of randomly selected CPs (Supplementary Figs. 1 and 2). Based on these data, the CPs can be divided into two distinct types. One category is featured by the absence of thermal decomposition near the melting points (T m ) of CPs and is referred to as TYPE I, such as Cyclo(-Phe-Pro) (CFP), Cyclo(-Pro-Tyr) (CPY), Cyclo(-Trp-Tyr) (CWY), and Cyclo(-Trp-Trp) (CWW) (fig. S1 ). Another type corresponds to CPs whose decomposition occurs during the melting process (referred to as TYPE II), which includes, but is not limited to, Cyclo(-Ala-Ala) (CAA), Cyclo(-Gly-Gly) (CGG), Cyclo(-Phe-Phe) (CFF), and Cyclo(-Leu-Phe) (CLF) (Supplementary Fig. 2). Next, we initially focused on TYPE I CPs as potential candidates for glass formation. To evaluate their suitability, we determined if they exhibit glass transition behavior by employing a second heating under the same conditions. This was carried out at identical heating and cooling rates of 10 °C min − 1 , using programmed DSC measurement under an inert nitrogen atmosphere. Here, CPY, derived from marine sponge Callyspongia fistularis symbionts with anticancer activity 22, 23 , was selected as the typical research model to demonstrate the preparation of CP glass (Fig. 1 b). The TGA-DSC curves of CPY exhibited no apparent weight loss during the entire melting process and a large gap between melting and decomposition temperature (Fig. 1 c), suggesting its excellent thermal stability. Such stability was further substantiated by the comparison between the mass spectrometry (MS) and 1 H nuclear magnetic resonance ( 1 H NMR) spectra of CPY glass and crystal (Supplementary Figs. 3 and 4), which confirmed that the melting process does not cause changes in the chemical structure. A noticeable glass transition temperature (T g ) at 71.8 °C was observed at the second upscan curve of DSC (Fig. 1 d), indicating the formation of an amorphous product. Such an amorphous nature was further confirmed by the broad diffraction peak centered at 2θ = 22.5°, which contrasts with the sharp X-ray diffraction peaks of CPY crystal with a high degree of crystallinity (Fig. 1 e). Moreover, such an obvious transition can also be verified by the polarized optical microscopy (POM) images showing the transition from crystalline powder to amorphous solid (Fig. 1 f and Supplementary Fig. 5). Scanning electron microscopy (SEM) images of CPY glass microbeads exhibit smooth, homogenous, and crack-free surfaces (Fig. 1 g), thereby affirming the surface homogeneity of the formed glass. Considering the importance of optical transmittance of cover glass for their application in various fields, we further investigate the transmittance spectrum of CPY Glass in the UV-vis region (Fig. 1 h). The figure shows that the transmittance at 448 nm–800 nm is higher than 80% for CPY glass, and it has a maximum transmission of 87.2% in the visible region. This was visually corroborated by the clear appearance of the phrase “CP Glass ” under the CPY glass layer. These results indicate that CP glass possesses good optical transmittance in the visible region, which is competitive with the glass used in ordinary commercial lighting applications (80% on average) 24 . The mechanical properties of CPY glass at the nanoscale were evaluated by the nanoindentation measurements. As illustrated by the load-displacement curve of CPY glass (Fig. 1 i), when the maximum load is 6.0 mN, the measured maximum indentation depth of CPY glass is 1053.3 nm, and the residual depth of the indentation is 836.3 nm upon unloading. Therefore, the CPY glass exhibits an elastic recovery performance with a relative elastic recovery rate of 20.6%, which is comparable to typical inorganic glasses such as sodium borate (23.8%), and borosilicate (24.8%) 25 . This result indicates that CPY glass maintains good elastic-plastic properties. The nanoindentation measurement also shows that Young’s modulus for the bulk CPY glass is 6.8 GPa (Fig. 1 j), which is as high as some reported CP crystals 14 and significantly higher than some natural fiber materials and common polymer materials 26 . In addition, hardness is another important property that can be determined from the indentation response of glass, which quantifies the resistance of glass to permanent deformation. To this end, we determined that the Vickers hardness for CPY glass is 0.32 GPa (Fig. 1 j), which is superior to polymethyl methacrylate (PMMA) (0.28 GPa) 27 . Collectively, these results compellingly indicate that CPs are robust for forming noncovalent glass with high thermal stability and robust mechanical properties. The formation mechanism of CP glass was investigated, with a particular focus on CPY glass as a representative example. To unravel the intermolecular interactions governing glass formation, the FTIR spectra of CPY in both its crystalline and glassy states were obtained (Fig. 2 a). In the spectra of CPY crystals, the narrow bands centered at 3304 and 3198 cm − 1 are assigned to the O-H and N-H stretching modes, respectively 28 . Additionally, the peaks at 1512, 1468, and 1440 cm − 1 correspond to the bending modes of N-H, indicating the existence of predominant hydrogen bonding interactions involving O-H and N-H. Further, combined with the strong peaks at 1666 and 1636 cm − 1 in the spectrum of CPY crystal, it can be concluded that CPY crystals are predominantly stabilized by C = O…H-O and C = O…H-N hydrogen bonds. Such networks have been confirmed by the hydrogen-bond arrays shown in the single-crystal structure of CPY (Fig. 2 c and Supplementary Figs. 6a, b). The two carbonyl oxygens of the diketopiperazine (DPK) ring form hydrogen bonds with the phenolic hydroxyl groups and the N-H group of the DPK ring in the neighbor (referred to as dimer 1 and dimer 2), as shown in Fig. 2 d. Furthermore, the well-defined peaks that manifest at 1609, 1591, and 1585 cm − 1 , originating from the aromatic C = C stretching modes, underscore the ordered aromatic arrangement of aromatic entities within the single-crystal of CPY. The underlying reasons for such aromatic ordering can be bifurcated: Firstly, for the CPY molecule within the lattice, the orientation of the aromatic ring in the tyrosyl residue is folded towards the DKP ring; Secondly, herringbone stacking of aromatic groups between neighboring CPY molecules results in the long-range ordered aromatic packing (Supplementary Figs. 6c, d). In contrast to the FTIR spectrum of the CPY crystal, the spectrum for CPY glass demonstrates broadened bands in the 3417 − 3031 cm − 1 , 1719 − 1619 cm − 1 , and 1600 − 1584 cm − 1 regions, suggesting the presence of multiple types of intermolecular interactions including hydrogen bonding and disordered aromatic interactions. This result has been evidenced by the random and irregular hydrogen-bond networks obtained through all-atom molecular dynamics (AAMD) simulation (Figs. 2 e, f), which is advantageous for forming disordered glass. Moreover, a notable red shift in the IR absorption frequencies of O-H and C = O in the glassy state compared to their crystalline counterparts points to the enhanced hydrogen bonding interaction of C = O…H-O 29 . In contrast, the blue-shifted vibration frequencies of N-H in CPY glass imply a weakened hydrogen bonding interaction of C = O…H-N (Fig. 2 b). Diving deeper with AAMD, and it's apparent that the frequency of the former bonds surpasses that of the latter in the post-formation CPY glass state (Fig. 2 f). Underpinning these findings, the more intense interaction energies and shorter lengths of the C = O…H-O hydrogen bonds dominate C = O…H-N 28, 30 . Moreover, the sharp contrast between the broad bands of C-H and aromatic C = C stretching modes in CPY glass and the well-defined peaks in CPY crystals underscores the transformation from ordered to chaotic aromatic configurations (Supplementary Fig. 7). A twofold rationale clarifies this transition. Initially, melting the CPY crystal disrupts the relatively weak hydrogen bonds and alters the conformation of CPY, as supported by the breakage of the C = O…H-N hydrogen bond and unfolding of the CPY conformation (Fig. 2 g). The AAMD simulation results demonstrate that more clusters stabilized by nonlinear and less-ordered hydrogen bonds existed in CPY glass (Supplementary Fig. 7), which inhibits directional growth and crystallization. Simultaneously, the high temperature that stabilizes the supercooled liquid facilitates hydrophobic aggregation. This process gives birth to multiple heterogeneous clusters, as validated by the tunable multicolor emission of CPY glass linked to the quantum confined effects (Supplementary Fig. 8) 13 . Multiple CPY clusters prevent the easy packing and diffusion of CPY molecules during the cooling process, thus inhibiting crystallization. Together, the pronounced disparities in FTIR features and molecular arrangement modes between CPY crystals and glass underline a pivotal principle: the interruption of long-range and directional intermolecular interactions, coupled with the emergence of less-ordered and nonspecific intermolecular interactions, promotes the formation of heterogeneous clusters and finally noncovalent glasses. Considering the importance of the thermal stability of amorphous materials for practical applications such as electronic and optoelectronic devices, we further explore the T g adjustability of CP glasses through modulating peptide structures (Fig. 3 a and Supplementary Fig. 9). When comparing with CPY, the introduction of Phe in place of Tyr makes the T g of CFP significantly decrease to 20.4 °C. This decline signifies that the absence of phenolic hydroxyl weakens the intermolecular interactions within CFP glass. Conversely, when Pro is replaced by Trp, the T g of CWY rises markedly to 114.8 °C. This rise in T g stems from the improved aromatic interactions of CWY, as supported by the elevated T g of CWW at 117.8 °C. This hypothesis has been validated by the interaction energies (IE) between stabilized CP dimer clusters obtained through density functional theory (DFT) calculations (Fig. 3 b). It becomes clear that the absolute IE values for most stable CFP, CPY, and CWY dimer clusters align with their T g trends, in which bigger the IE values are, higher their T g are. Whereas the CWW dimer cluster exhibits a divergent trend of increased T g but with a relatively lower IE value. Such an exception is most likely due to the enhanced aromatic interactions between CWW clusters. Beyond the role of intermolecular interactions in the T g of glass, the molecular motion of CP clusters is another factor that cannot be ignored 31 . For CPs with bulkier residues, the translational, rotational, and vibrational motions of CP molecules are more restricted, leading to a higher T g . Thus, the T g of CP glass can be tailored according to the type and size of CP residues. Notably, T g values of CWW and CWY exceed those of previously reported organic glass based on polymers such as commercial polymethyl methacrylate (T g = 107.0 °C) 32 , and small molecules such as 1,3-bis-(1-naphthyl)-5-(2-naphthyl) benzene (T g = 73.9 °C) and indomethacin (T g = 41.9 °C) with exceptional thermodynamic and kinetic stability 33 . The prominent thermostability of CP glass might significantly facilitate its wide-ranging applications in biomedical interfaces, particularly where the stability above human body temperature is paramount. We evaluate the glass-forming ability (GFA) of CPs through the ratio of T g /T m , which characterizes the crystallization-resistant ability of the supercooled liquid during quenching. According to Kauzmann’s 2/3 law, systems with T g /T m values larger than 2/3 are usually regarded as possessing superior GFA 34 . Given that all T rg values for the selected CPs surpass this 2/3 benchmark (Fig. 3 c and Supplementary Table 1), it suggests that such CPs’ supercooled liquids are strong glass-formers, which can effectively hinder the crystallization tendency. In addition to T g /T m describing the crystallization-resistant ability of the glass former, another critical parameter involves the heat capacity jump during the glass transition (ΔC p ), which is inversely correlated with both the glass network connectivity and the number of the topological constraints 35 . It can be found that CPY glass possesses the smallest ΔC p , while CWY and CWW glass possess relatively larger ΔC p (Supplementary Table 1). This variance can be ascribed to the distinctive local structures with different glass network connectivity. Therefore, it is inferred that more discrete molecular cluster structures exist within the CWY and CWW glass. Of particular note is the observation that the order of ΔC p values inversely mirrors that of T g , suggesting a possible decline in glass network connectivity with increased aromatic interactions. Subsequently, the thermodynamic fragility of CP glass was calculated based on an empirical correlation between fragility and thermodynamic parameters proposed by Angell et al. 36 , which is linked to the aging behavior and nonexponential relaxation of viscous liquids 37 . In the classification of strong and fragile liquids, liquids considered "strong" are those with minimal structural changes around their T g 38 . Strong liquids are often characterized by self-reinforcing networks resistant to temperature-induced structural changes. Fragile liquids usually lack directional bonding and often possess either ionic or aromatic attributes 39 . Upon analysis, it can be found that all the m-values of CP glasses are in the range of 90 to 99, signifying their inclination towards forming glasses with relative ductility 40 . These values are close to those of most polymers, some small organic molecules with abundant aromatic groups, and inorganic glass formers with strong ionic interactions 41, 42 . Yet, these values markedly deviate from those of traditional silicate glass-formers, water, and small organic molecules with strong hydrogen bonding interactions 41, 43–45 . This disparity can be ascribed to the synergy of hydrogen bonds, aromatic interactions, and hydrophobic effects 3, 46 . Notably, the abundant aromatic and hydrophobic interactions are responsible for the relatively higher m-values of CWY and CWW glasses compared to CFP and CPY glasses (Fig. 3 c and Supplementary Table 1). This indicates that CP glasses with different fragility can be engineered by precisely modulating the types of amino acids in CPs. The above results highlight TYPE I CPs capable of forming stable glass through direct melting-quenching of CP raw powders at heating and cooling rates of 10 °C min − 1 . Yet, there exists another type of CPs, referred to as TYPE III, that struggles to form stable glass at identical rates, such as Cyclo(-Gly-Pro) (CGP), Cyclo(-Leu-Pro) (CLP), Cyclo(-Pro-Thr) (CPT), and Cyclo(-Phe-Ser) (CFS) with T m <T d (Supplementary Fig. 10). Taking these four CPs as an example (Fig. 4 a), pronounced endothermic peaks were observed in the second upscan DSC curves of CGP, CLP, and CFS, indicating that CGP, CLP, and CFS crystals formed rather than glass during the first cooling process. For the second upscan DSC curve of CPT, a glass-transition phenomenon was first observed at T g =14.8 °C, followed by two exothermic peaks because of cold crystallization. According to the classification proposed by Trasi et al 47 , this group of unstable CP glass is rather heterogeneous. In principle, any liquid can be solidified into a glass with a sufficiently fast cooling rate. The slowest rate of bypassing crystallization to form glass characterizes how easily a system can be vitrified 48 . Despite our efforts to increase the cooling rate to inhibit the crystallization of CPs, we failed to achieve stable glass for such CPs. For instance, even at a 40 °C min − 1 cooling rate, obtaining stable CLP glass remained elusive (Supplementary Fig. 11). Considering the random molecular arrangement devoid of long-range ordering in stable CP glass, it is supposed that the entropy maximum of the system can facilitate the formation of stable glass. With this rationale, we attempted to melt and quench the mixtures of different CPs to hamper the crystallization of individual CPs. The sequential appearance of glass transition, cold crystallization, and melting in the second upscan DSC curves of mixtures encompassing two or three types of CPs revealed that unstable glass is formed with increased system entropy (Figs. 4 b and c). Further increasing the number of CP types in the mixture, stable glass can be achieved ultimately (Fig. 4 d). The emergence of individual CPs in the ESI-MS spectrum confirmed that all the CPs are involved in the multicomponent glass (Supplementary Fig. 12). Notably, achieving stable glass based on the mixture of multiple CPs is not a coincidence. Such a strategy has been also applied to fabricating glass containing crystallization-favorable CPs with four or more CP species (Supplementary Figs. 13–16). Taken together, the increasing entropy effect resulting from the increasing number of CP components plays a crucial role in achieving stable multicomponent CP glass (Fig. 4 e). To understand the role of entropy in glass formation, we calculate the configurational entropy ( \(Δ S\) ) of different CP mixtures. The individual CPs are considered ideal colloidal spheres to simplify the calculation. When 2 to 6 CPs are mixed at equimolar amounts, \(Δ S\) increases from 0.69 \(R\) to 1.79 \(R\) , where \(R\) denotes the ideal gas constant. Drawing parallels from the broadened definition of high-entropy alloy ( \(Δ S\) >1.36 \(R\) ) 49 , we define the glass composed of four or more equimolar CPs as high-entropy CP (HECP) glass, given that their \(Δ S\) stands at a minimum of 1.39 \(R\) . Such an increase in conformational entropy indicates an increasing degree of disorder in HECP glass consisting of equimolar CPs. To decipher the molecular mechanism underlying the formation of HECP glass, we examined the FTIR and Raman spectra of quenched individual CP samples and HECP glass (Figs. 4 f and 4 g). Well-defined peaks characterized by O-H, N-H, C-H, and C = O stretching vibration modes and the sharp profile corresponding to the benzene ring of CFS were observed in the FTIR and Raman spectra of individual quenched CP products. Such observations hint at the presence of directional intermolecular interactions, including specific hydrogen bonding interactions and ordered-stacking interactions, which facilitate the long-range ordered molecular arrangements. In contrast, such characteristic peaks became weaker or even vanished, merging into broader absorption peaks in the vibration spectra of HECP glass. This indicates the disruption of original ordered molecular arrangements and the emergence of a more chaotic molecular packing paradigm fostered by diverse intermolecular interactions among varied CPs. A possible local random molecular packing pattern within HECP glass was depicted in Fig. 4 h. Such random arrangements promote the generation of heterogeneous CP clusters, as verified by the multicolor fluorescence imaging of the HECP glass (Supplementary Fig. 17). The coexistence of multiple CP clusters can effectively increase the configurational entropy of supercooled liquid consisting of CP mixture, which retards molecular diffusion, effectively retarding relaxation, hinder crystallization, and further facilitate the formation of glass with improved thermal stability 50 . Notably, when incorporating CPs with good glass-forming ability, stable glass could be achieved even with fewer than four components (Supplementary Figs. 18 and 19). More importantly, the entropy-increasing strategy is not limited to typical CPs but also extends to glasses containing thermally labile CPs, such as CFF, CAA, and CGG, which are characterized by severe decomposition before or near the T m . Two sets of multicomponent CP glass compositions, namely CFF, CFW, CPY, CWY, CWW or CAA, CGG, CPY, CWY, CWW, were successfully fabricated with an equimolar ratio (Supplementary Figs. 20 and 21). Impressively, neither of these glass systems exhibited any signs of thermal decomposition. Delving deeper into the T g of HECP glass, proline-rich CP mixtures tend to produce glass with a T g no more than 40 °C. In comparison, tryptophan-rich CP mixtures facilitate the formation of glass with a T g higher than 100 °C (Supplementary Fig. 22). Such a distinction demonstrates the potential to craft a spectrum of glasses with variable T g values by precisely manipulating the amino acid types of peptides and the number of compositions. Taken together, these multicomponent HECP glasses, especially those with elevated T g , are poised to revolutionize fields such as organic light-emitting diode displays, where there is a dire need for operational stability, compositional flexibility, and macroscopic homogeneity 51 . We subsequently delved into the effect of high entropy on the mechanical properties of CP glass. For this purpose, we chose three representative glasses, CPY glass, CFF-CPY-CFW-CWY-CWW HECP glass (referred to as CFF-containing HECP glass), and CAA-CGG-CPY-CFW-CWY HECP glass (referred to as CGG-containing HECP glass), for comparison in the following nanoindentation tests. As illustrated by the load-displacement curves, the HECP glass exhibits a shallower indentation depth compared to the individual CPY glass under the load of 450 mN (Fig. 5 a). This evidences a superior resistance to deformation in the HECP glass as opposed to the individual CP glass. Furthermore, the Young's modulus and Vickers hardness of HECP glass are superior to those of individual CPY glass (Fig. 5 b, c) and some natural fibers and commercial polymer materials, but lower than those of commonly used inorganic glasses. These results suggest that HECP glass represents a novel type of glass, bridging the gap between traditional polymer and inorganic glass. Notably, the CGG-containing HECP glass demonstrates the minimum indentation depth while maximum Young's modulus and Vickers hardness. The significant improvement of mechanical properties may be ascribed to the compact and interconnected architecture inherent to HECP glass (Fig. 5 d). On the one hand, different CPs, due to variations in their amino acid compositions as shown in Supplementary Table 2, have disparate sizes. These dimensionally varied CPs inherently favor densely packed configurations, potentially resulting in the sluggish diffusion of CPs. Concurrently, the coexistence of multiple types of CPs augments the diversity of intermolecular interactions, thereby fostering a denser network within HECP glass. Such a promoted network connectivity can be attributed to the decrease in fragility upon mixing 52 . Therefore, the synergistic effect of sluggish diffusion and hyperconnected network architectures is responsible for the overall enhancement in mechanical performances of HECP glass. Conclusions We report the fabrication of stable noncovalent glass based on naturally derived CPs by manipulating their conformation complexity of CP clusters. It was discovered that efficient crystallization inhibition, by increasing the conformation entropy of supercooled liquid, is critical to the formation of stable CP glass. In comparison to their singular counterparts, HECP glass, made up of a multitude of CP components, consistently demonstrate an aptitude for resisting both crystallization and thermal decomposition. They also boast improved mechanical attributes due to the synergistic effect of network connectivity, structural diversity, and close packing patterns inherent to HECP glasses. The Young’s modulus and Vickers hardness of HECP glass are superior to some naturally biological materials and commercial polymers, yet they remain inferior to the traditional inorganic glass. These unique mechanical characteristics position the HECP glass not just as an addition, but as a revolutionary entrant in the domain of traditional glasses and amorphous materials. This endeavor marks a seminal progress in the quest to conceive noncovalent glasses derived from naturally prevalent CPs, transcending their existing crystalline counterparts, and paving the way for the next-generation biomolecular materials. Taking advantage of the decent pharmacological activities and optoelectronic properties of CPs, it is believed that such avant-garde glasses with stellar thermal stability and mechanical property would significantly spearhead the conceptualization and realization of biorecyclable noncovalent glasses suitable for biomedical devices and wearable smart devices. Beyond pioneering a new class of functional glass, this study sheds light on the quintessential molecular traits characterizing high-entropy noncovalent glasses, representing a landmark discovery in the landscape of amorphous material science. Declarations Data availability All data are available in the main text or the Supplementary Information. Additional requests can be made to the corresponding author. Acknowledgement This work was supported by National Science Fund for Distinguished Young Scholars of China (No. 22025207), National Natural Science Foundation of China (No. 22172172, 22372174, and 22232006), Youth Innovation Promotion Association of CAS (Grant No. 2022049), China Scholarship Council (CSC, 202104910187), IPE Project for Frontier Basic Research (Grant No. QYJC-2022-011) and Natural Science Foundation of Hebei Province (No. B2020103036 and B2020103025). Author contributions X.Y. and C. Y. developed the concept of high-entropy noncovalent glass and designed the experiments. C.Y., W. F., and S. C. performed the experiments. C.Y., W. F. R. X., and X. Y. analyzed the experimental data. C.Y. and P. Z. designed the theoretical model and performed the simulations. C.Y. and X. Y. wrote the manuscript. All authors discussed the results and commented on the manuscript. Competing interests The authors declare no competing interests. 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Ràfols-Ribé, J. , et al. , High-performance organic light-emitting diodes comprising ultrastable glass layers. Sci. Adv. 4 , eaar8332 (2018). Gong, H. , et al. , Kinetic fragility of binary and ternary glass forming liquid mixtures. Eur. Phys. J. E 34 , 86 (2011). Willcott, M. R., MestRe Nova. J. Am. Chem. Soc. 131 , 13180-13180 (2009). Jiang, B. , et al. , High-entropy-stabilized chalcogenides with high thermoelectric performance. Science 371 , 830-834 (2021). Van Der Spoel, D. , et al. , GROMACS: Fast, flexible, and free. J. Comput. Chem. 26 , 1701-1718 (2005). Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A. & Case, D. A., Development and testing of a general amber force field. J. Comput. Chem. 25 , 1157-1174 (2004). Wang, J., Wang, W., Kollman, P. A. & Case, D. A., Antechamber: an accessory software package for molecular mechanical calculations. J. Am. Chem. Soc 222 , U403 (2001). Ogliaro, F. , et al. , Gaussian 09, Revision A. 02. Gaussian. Inc.: Wallingford, CT (2009). Boys, S. F. & Bernardi, F., The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors. Mol. Phys. 19 , 553-566 (1970). Lu, T. & Chen, F., Multiwfn: A multifunctional wavefunction analyzer. J. Comput. Chem. 33 , 580-592 (2012). Materials And Methods Materials All the cyclic peptides used in this work were purchased from Bachem. 1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP) was purchased from Innochem (Beijing). Water was prepared in a double-stage Millipore Milli-Q Plus purification system (Merck Millipore, Burlington, VT, United States). Thermogravimetric analysis The thermogravimetric curves of all the CP powders were obtained using a TGA/DSC 3+ series instrument (Mettler Toledo, Switzerland) with an inert protective gas (N 2 ) at a heating rate of 10 °C min -1 . Baseline adjustment was first performed using two empty platinum crucibles. Then, TGA measurements were conducted by placing the CP powders in one platinum crucible on the "S" side, with an empty crucible placed on the "R" side as a reference. The samples were heated from room temperature to 500 °C to determine T m and T d . Glass preparation The preparation of CP glass is as follows: 10 mg CP powder was heated to the temperature above their T m and maintained for 5 min at this temperature, then quickly cooled to room temperature. All the above operations are performed in a glove box. The CP powders were exchanged in the oxygen-free glove box for two weeks to eliminate the oxygen adsorbed onto the powders. The preparation of HECP glass is as follows: Different CP powders were mixed in an equimolar ratio and dissolved in HFIP to get a transparent solution. The solution within an open centrifuge tube was placed in a fume hood to dry. Then, the dried powders were moved to the oxygen-free glove box for two weeks to eliminate the oxygen adsorbed. Finally, HECP glasses were prepared through the same procedure as the preparation of individual CP glasses. Differential scanning calorimetry DSC measurements were carried out with a DSC 1 instrument (Mettler Toledo, Switzerland). The tests were carried out according to the following steps: (1) The individual or mixed CP powders were placed in an Al crucible. (2) The samples were heated from room temperature (T 0 ) to a temperature (T 1 ) higher than T m but lower than T d to get the supercooled liquids of individual CPs or mixed CPs. (3) Such melted liquids were kept isothermal for 5 min. (4) The above liquids were cooled to a temperature (T 2 ) no higher than T 0 , followed by an isothermal procedure at T 2 for 10 min. (5) Finally, the second heating-cooling cycle between T 2 and T 1 was performed. The T m was extracted from the first heating scan (Upscan1), while the T g was extracted from the second heating scan (Upscan2). All the heating and cooling rates were 10 °C min –1 , except those specified in this work. The values of ΔC p were calculated as the difference of heat capacity during glass transition in the second upscan curves. PXRD measurement XRD patterns of CP powders and glass were identified by an X-ray diffractometer with a high brightness source Rigaku SmartLab 9kW (Rigaku, Japan) equipped with a Cu filter and a Cu Kα1 radiation source (λ = 1.5406 Å). The samples were placed in clean silicon slices. The measurements were made in a 2θ range of 10°-50° at ambient temperature with a step of 0.01° (2θ) and a scanning rate of 10° min -1 . Bright-field and POM imaging Bright-field and cross-polarized microscopy images were acquired on a BX53 polarized microscope system (Olympus, Japan). Fluorescence spectroscopy Solid fluorescence spectra of CPY glass were obtained using a FluoroMax+ spectrofluorometer (Horiba, Japan). Excitation and emission bandwidths were 5 nm, respectively. The CPY glass sample was placed between flat and clean quartz sheets with quantitative grooves. HR-ESI-MS measurement High-resolution electrospray ionization mass spectra (HR-ESI-MS) of CPY crystal and glass as well as HECP glass were collected by a 9.4T FT-ICR-ESI MS (Bruker). The MS scan range was set from m/z 100 to 600. The samples including the CPY crystal and glass as well as HECP glass were dissolved in ethanol solution. NMR spectroscopy The solution 1 H NMR spectra of CPY crystal and glass samples were recorded at room temperature on a 600-MHz Avance spectrometer equipped with a triple resonance cryogenic probe using a simple 1D pulse sequence (Bruker, Germany). Chemical shifts were referenced to the residual solvent proton signals of DMSO-d6. The obtained spectra were further analyzed with the MestreNova software 53 . FT-IR measurement Attenuated total reflection FT-IR spectra of the CP powders and glasses were measured on a Bruker VERTEX 70v infrared spectrophotometer. Each spectrum was recorded by performing 32 scans between 4000 and 400 cm -1 . UV-Vis-NIR transmittance/absorption measurement The transmittance and absorption spectra of the CPY glass in the UV-visible region (200–800 nm) were carried out on a SPECORD200 spectrophotometer by positioning the glasses (ca. 2 mm thick) perpendicular to the incident beam. Fluorescence microscope observation The fluorescence images of CP glasses under the irradiation were taken with an OLYMPUS IX71 fluorescence microscope (Tokyo, Japan). Nanoindentation measurement The hardness and Young’s modulus of the samples were measured by nanoindenter (Keysight technologie-G200) with a depth of 1 mm, each sample was subjected to at least three indentations using a three-sided pyramidal (Berkovich) diamond indenter. Nanoindentation measurements for the comparison of CPY glass with CFF-containing and CGG-containing HECP glass were performed using the maximum load of 450 mN. When the load was reduced to 10% of the maximum load, thermal drift measurements are taken before the indenter is fully retracted. The loading and unloading times were both 10 s. Calculation of configurational entropy (ΔS ) The configurational entropy ΔS of the entropy-stabilized CPs glass is calculated based on the following equation 54 : Computational methods All-atom molecular dynamics (AAMD) simulations were conducted on the Gromacs package (Version 5.1.4) 55 . The CPY molecule was modeled by the general AMBER force field (GAFF) 56 . The molecular electrostatic potential of the CPY was obtained based on the optimized geometry at the HF/6–31g (d) level of theory, which derives the GAFF parameters for subsequent AAMD. The partial charge was computed on the Antechamber package based on the restrained electrostatic potential (RESP) formalism 57 . In this study, AAMD simulations on 144 CPY molecules consisting of 3Í3Í1 CPY lattices were performed. First, the system underwent minimization using the conjugate-gradient algorithm, employing a maximum force tolerance of 200 kJ mol -1 . To achieve equilibrium of the temperature and volume, 400 ps of a constant–volume, constant–temperature (NVT) simulation and 400 ps of isothermal-isobaric (NPT) simulations were performed. Subsequently, the entire system underwent a heating, maintenance, and cooling process to simulate annealing. The temperature variations during annealing are depicted in fig. S23. The equations of motion were integrated using the leapfrog algorithm with a time step of 2 fs. For temperature control and pressure regulation, the velocity rescale thermostat and the isotropic Parrinello-Rahman barostat were employed, with relaxation times of 0.4 ps and 2.0 ps, respectively. Electrostatic forces were calculated using the particle-mesh Ewald approach, applying a cutoff of 1.0 nm. Additionally, a 1.0 nm cutoff was utilized for van der Waals forces. The LINCS algorithm was employed at each step to preserve bond lengths. Density functional theory (DFT) calculations were employed to investigate the intermolecular interactions between CP dimers. The stable geometries of CP monomer and CP dimers were obtained through the optimization of initial conformations using the Gaussian 09 package 58 . Such complexes were optimized in a vacuum at the wB97XD/6-31G (d) level of theory without symmetry constraints. The harmonic vibrational frequency calculations on the optimized geometries were also performed to ensure the structures at local minima. Interaction energies are defined as the difference between the energy of the dimers and the sum of the CP monomers and are corrected with basis set superposition errors (BSSE) via the counterpoise procedure 59 . Molecular diameters of CGG, CAA, CFF, CFW, CPY, CWY, and CWW were calculated based on the Multiwfn 3.8 60 . Such CPs were first optimized at the HF/6–31g (d) level of theory. Additional Declarations There is NO Competing Interest. Supplementary Files SupportingInformation.docx Cite Share Download PDF Status: Published Journal Publication published 26 Aug, 2024 Read the published version in Nature Nanotechnology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3347593","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":232466633,"identity":"d90b7a72-28a7-4b17-8746-9c4500b4b5df","order_by":0,"name":"Xuehai 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1","display":"","copyAsset":false,"role":"figure","size":318956,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCharacterization of CP glass formed using a single component, CPY. a, \u003c/strong\u003eSchematic illustration showing the noncovalent glass preparation procedure based on CPs with T\u003csub\u003ed\u003c/sub\u003e\u0026gt;T\u0026gt;T\u003csub\u003em\u003c/sub\u003e. \u003cstrong\u003eb,\u003c/strong\u003e The chemical structure of CPY. \u003cstrong\u003ec,\u003c/strong\u003e The TGA-DSC curves of CPY crystal. \u003cstrong\u003ed, \u003c/strong\u003eThe DSC curve during the second upscan of CPY. \u003cstrong\u003ee,\u003c/strong\u003e XRD pattern of CPY glass, as compared with that of CPY crystal.\u003cstrong\u003e f,\u003c/strong\u003e Bright-field and POM images of CPY glass. \u003cstrong\u003eg,\u003c/strong\u003e SEM image of CPY glass beads. \u003cstrong\u003eh,\u003c/strong\u003e Optical transmittance spectrum of CPY glass in the UV-visible region. \u003cstrong\u003ei,\u003c/strong\u003e The load-displacement curve of CPY glass. \u003cstrong\u003ej, \u003c/strong\u003eYoung’s modulus and hardness of CPY glass.\u003c/p\u003e","description":"","filename":"floatimage1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3347593/v1/149da7dbeb4ffb79dea973b7.jpg"},{"id":43083662,"identity":"98ef97d7-275a-42d8-b846-f72121ab6eb7","added_by":"auto","created_at":"2023-09-13 16:13:14","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":279964,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMolecular mechanism underlying CPY glass formation. a, \u003c/strong\u003eFT-IR spectrum of CPY glass, as compared with that of CPY crystal. \u003cstrong\u003eb,\u003c/strong\u003eWavenumber shifts of the crucial groups involved in the hydrogen bonding interactions between CPY molecules. \u003cstrong\u003ec,\u003c/strong\u003e Molecular packing pattern within the single crystal of CPY. \u003cstrong\u003ed,\u003c/strong\u003e Two dominant dimers existed in the single crystal of CPY. \u003cstrong\u003ee, \u003c/strong\u003eMolecular packing state within CPY glass obtained through AAMD simulations. \u003cstrong\u003ef,\u003c/strong\u003e Statistics of hydrogen bond types existed in single crystal and glass of CPY. \u003cstrong\u003eg,\u003c/strong\u003e The newly formed dimer in CPY glass through partial breakage of C=O…H-N hydrogen bonds of dimer 2 within CPY single crystal. The left CPY molecule marked with orange Carbon atoms denotes that the molecular conformation has changed after glass formation. Blue and red dotted lines shown in c, d, e, and g represent different types of hydrogen bonds.\u003c/p\u003e","description":"","filename":"floatimage2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3347593/v1/54aeac3083cedb5b148b4b2d.jpg"},{"id":43083664,"identity":"2181ea2f-2a72-44c1-8316-682692145dc9","added_by":"auto","created_at":"2023-09-13 16:13:14","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":190626,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTunable glass transition behaviors.\u003c/strong\u003e \u003cstrong\u003ea,\u003c/strong\u003e Tunable T\u003csub\u003eg\u003c/sub\u003e of CP glass through modulating amino acid types of peptides. \u003cstrong\u003eb,\u003c/strong\u003e The reduced temperature (T\u003csub\u003eg\u003c/sub\u003e/T\u003csub\u003em\u003c/sub\u003e) and fragility of CPs. \u003cstrong\u003ec,\u003c/strong\u003e Stable CP dimers obtained through DFT calculations. The energy values denote the interaction energies between these dimers. The dashed lines represent the hydrogen bonds between CP dimers.\u003c/p\u003e","description":"","filename":"floatimage3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3347593/v1/e36477dcfa5fcd3f4f93982b.jpg"},{"id":43083669,"identity":"ae612a9b-2be8-4215-96bb-ae7580cd8faa","added_by":"auto","created_at":"2023-09-13 16:13:16","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":350798,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFormation and characterization of high-entropy CP glass. a-e, \u003c/strong\u003eExperimental evidence and schematic illustration showing the concept of glass formation facilitated by entropy increasing. FT-IR (\u003cstrong\u003ef\u003c/strong\u003e) and Raman (\u003cstrong\u003eg\u003c/strong\u003e) spectra of CGP, CLP, CPT, CFS powders, and glass formed through melting-quenching of their mixtures.\u003cstrong\u003e h,\u003c/strong\u003e Possible molecular patterns within HECP glass inferred from the results of f and g.\u003c/p\u003e","description":"","filename":"floatimage4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3347593/v1/37dca6da6117b074948f8c97.jpg"},{"id":43083667,"identity":"a767f3b2-016a-43a9-ab1c-f65fbd3b9d8d","added_by":"auto","created_at":"2023-09-13 16:13:15","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":317293,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHigh-entropy-enhanced mechanical properties of CP glasses. a, \u003c/strong\u003eThe load displacement into the surface curve of HECP glasses and individual CPY glass. \u003cstrong\u003eb, \u003c/strong\u003eComparison of\u003cstrong\u003e \u003c/strong\u003eYoung’s modulus between HECP glasses and traditional materials. \u003cstrong\u003ec,\u003c/strong\u003e Comparison of\u003cstrong\u003e \u003c/strong\u003eVickers hardness between HECP glasses and traditional materials. \u003cstrong\u003ed, \u003c/strong\u003eSchematic illustration showing the microscopic structural characteristics of HECP glass and individual CP glass.\u003c/p\u003e","description":"","filename":"floatimage5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3347593/v1/05548c12036ad9529441dfcc.jpg"},{"id":63344913,"identity":"80e28da1-c9cb-447c-9bf1-a9a30c2f4f78","added_by":"auto","created_at":"2024-08-27 07:16:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2192090,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3347593/v1/12a2591e-8a88-4cfa-a766-3a7d40dc4b30.pdf"},{"id":43083665,"identity":"b7051e0a-87e6-4ac9-9f0a-22533c77721a","added_by":"auto","created_at":"2023-09-13 16:13:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":5514548,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupportingInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-3347593/v1/e096aedc892cd9b9dec9cc84.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Cyclic Peptide High-Entropy Noncovalent Glass","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGlass is the material that humans shape, and the material that also shapes humans. With its unparalleled versatility and technical capabilities, glass, in its many guises, has fostered numerous cultural and scientific advancements\u003csup\u003e1\u003c/sup\u003e. In the context of sustainability and circular economy, the design and development of next-generation glass should follow the principles that are benign, renewable, and degradable rather than toxic, depleting, and persistent\u003csup\u003e2\u003c/sup\u003e. One such promising avenue is the development of noncovalent biomolecular glasses stabilized by noncovalent interactions between amino acid and peptide derivatives\u003csup\u003e3\u003c/sup\u003e. Such glasses present a striking contrast to traditional inorganic and polymer glasses that rely on strong ionic and covalent interactions Their notable biocompatibility and biodegradability make them an ideal alternative for biodegradable and biorecyclable glasses. When envisioning applications that intersect with biology, such as implantable medical devices or wearable smart devices, it is essential that these noncovalent glasses resist enzymatic hydrolysis throughout their functional lifespan\u003csup\u003e4\u003c/sup\u003e. Moreover, these glasses should also endure the thermal treatments inherent to the device manufacturing processes\u003csup\u003e5\u003c/sup\u003e. Therefore, developing noncovalent glass that can robustly perform in challenging physiological conditions while ensuring minimal rejection is of paramount importance.\u003c/p\u003e \u003cp\u003eCyclic peptides (CPs) feature a cyclic backbone containing two or more amino acids, imparting them with increased stability and resistance to enzymatic degradation compared to their linear counterparts\u003csup\u003e6\u0026ndash;9\u003c/sup\u003e. These CPs are ubiquitous in natural organisms such as plants, animals, and microorganisms, especially in marine microorganisms\u003csup\u003e10\u003c/sup\u003e. Furthermore, CPs have demonstrated a wide range of diverse biological and pharmacological activities such as antimicrobial, anticancer, antiviral, immunosuppressive, and anti-inflammatory properties. These activities are attributed to their excellent binding affinity, target selectivity, and low toxicity\u003csup\u003e11\u0026ndash;13\u003c/sup\u003e. Therefore, CPs offer a versatile platform for designing and fabricating noncovalent glass for diverse biomedical and other high-tech applications. However, research on CPs has been primarily focused on their long-range ordered self-assemblies, especially in the crystalline state\u003csup\u003e14\u0026ndash;16\u003c/sup\u003e. The relatively uncharted territory of the glassy state of CPs can be ascribed to the remarkable structural rigidity of the cyclic scaffold and superior hydrogen-bond-forming ability\u003csup\u003e17\u0026ndash;19\u003c/sup\u003e. Despite this, the ongoing quest is to develop an efficient and robust approach to achieve stable CP glass with tailored properties for specific applications. One key hurdle is that the generation of critical crystal nuclei must be effectively inhibited to achieve CP glass. It has been reported that competition between clusters with similar energy levels decreases the probability of selecting viable crystal structures and thereby promotes glass formation\u003csup\u003e20, 21\u003c/sup\u003e. Inspired by this, we postulate that CP glass might be achieved when multiple CP clusters with similar energy coexist.\u003c/p\u003e \u003cp\u003eIn this work, we have created a series of CP glasses with tunable glass transition temperatures and mechanical properties through modulating the conformational complexity of CP clusters and increasing the conformational entropy. Taking advantage of the significant effect of temperature on CP conformation, we melted the crystalline CPs to disrupt the original long-range intermolecular interactions before observing any thermal decomposition and facilitated the generation of conformational polymorphisms of CP clusters in the supercooled liquid. Upon rapid cooling, these disordered conformers are kinetically preserved, leading to the formation of glass. Further increasing disorder by mixing various CPs makes it possible to achieve a stable high-entropy CP (HECP) glass. Additionally, the concept of HECP glass could be extended to fabricating glass incorporating CPs that are highly crystalline or thermally labile. The increase in conformation entropy, resulting from mixing multiple components, significantly impedes crystallization and prevents the decomposition of individual CPs, ultimately leading to the formation of stable HECP glass. The obtained HECP glass exhibits enhanced mechanical properties compared to individual CP glasses due to the promoted connectivity of the glass network. These findings provide valuable insights into the essential role of entropy in the formation and stabilization of biomolecular glasses. Moreover, these findings broaden the potential applications of biomolecular materials, enabling the development of innovative technologies based on noncovalent glasses that possess enhanced versatility and functionality.\u003c/p\u003e"},{"header":"Results and discussions","content":"\u003cp\u003eThe supercooled liquid of CPs is essential for achieving bulk glasses through the melting-quenching method (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). To avoid the decomposition of CPs during the melting process, we first conducted a series of measurements using thermogravimetric analyzer combined with a differential scanning calorimeter (TGA-DSC) to evaluate the melting point (T\u003csub\u003em\u003c/sub\u003e) of randomly selected CPs (Supplementary Figs.\u0026nbsp;1 and 2). Based on these data, the CPs can be divided into two distinct types. One category is featured by the absence of thermal decomposition near the melting points (T\u003csub\u003em\u003c/sub\u003e) of CPs and is referred to as TYPE I, such as Cyclo(-Phe-Pro) (CFP), Cyclo(-Pro-Tyr) (CPY), Cyclo(-Trp-Tyr) (CWY), and Cyclo(-Trp-Trp) (CWW) (fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Another type corresponds to CPs whose decomposition occurs during the melting process (referred to as TYPE II), which includes, but is not limited to, Cyclo(-Ala-Ala) (CAA), Cyclo(-Gly-Gly) (CGG), Cyclo(-Phe-Phe) (CFF), and Cyclo(-Leu-Phe) (CLF) (Supplementary Fig.\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eNext, we initially focused on TYPE I CPs as potential candidates for glass formation. To evaluate their suitability, we determined if they exhibit glass transition behavior by employing a second heating under the same conditions. This was carried out at identical heating and cooling rates of 10 \u0026deg;C min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, using programmed DSC measurement under an inert nitrogen atmosphere. Here, CPY, derived from marine sponge \u003cem\u003eCallyspongia fistularis\u003c/em\u003e symbionts with anticancer activity\u003csup\u003e22, 23\u003c/sup\u003e, was selected as the typical research model to demonstrate the preparation of CP glass (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). The TGA-DSC curves of CPY exhibited no apparent weight loss during the entire melting process and a large gap between melting and decomposition temperature (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec), suggesting its excellent thermal stability. Such stability was further substantiated by the comparison between the mass spectrometry (MS) and \u003csup\u003e1\u003c/sup\u003eH nuclear magnetic resonance (\u003csup\u003e1\u003c/sup\u003eH NMR) spectra of CPY glass and crystal (Supplementary Figs.\u0026nbsp;3 and 4), which confirmed that the melting process does not cause changes in the chemical structure. A noticeable glass transition temperature (T\u003csub\u003eg\u003c/sub\u003e) at 71.8 \u0026deg;C was observed at the second upscan curve of DSC (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed), indicating the formation of an amorphous product. Such an amorphous nature was further confirmed by the broad diffraction peak centered at 2θ\u0026thinsp;=\u0026thinsp;22.5\u0026deg;, which contrasts with the sharp X-ray diffraction peaks of CPY crystal with a high degree of crystallinity (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee). Moreover, such an obvious transition can also be verified by the polarized optical microscopy (POM) images showing the transition from crystalline powder to amorphous solid (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ef and Supplementary Fig.\u0026nbsp;5). Scanning electron microscopy (SEM) images of CPY glass microbeads exhibit smooth, homogenous, and crack-free surfaces (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eg), thereby affirming the surface homogeneity of the formed glass. Considering the importance of optical transmittance of cover glass for their application in various fields, we further investigate the transmittance spectrum of CPY Glass in the UV-vis region (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eh). The figure shows that the transmittance at 448 nm\u0026ndash;800 nm is higher than 80% for CPY glass, and it has a maximum transmission of 87.2% in the visible region. This was visually corroborated by the clear appearance of the phrase \u0026ldquo;CP Glass\u003cem\u003e\u0026rdquo;\u003c/em\u003e under the CPY glass layer. These results indicate that CP glass possesses good optical transmittance in the visible region, which is competitive with the glass used in ordinary commercial lighting applications (80% on average)\u003csup\u003e24\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe mechanical properties of CPY glass at the nanoscale were evaluated by the nanoindentation measurements. As illustrated by the load-displacement curve of CPY glass (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ei), when the maximum load is 6.0 mN, the measured maximum indentation depth of CPY glass is 1053.3 nm, and the residual depth of the indentation is 836.3 nm upon unloading. Therefore, the CPY glass exhibits an elastic recovery performance with a relative elastic recovery rate of 20.6%, which is comparable to typical inorganic glasses such as sodium borate (23.8%), and borosilicate (24.8%)\u003csup\u003e25\u003c/sup\u003e. This result indicates that CPY glass maintains good elastic-plastic properties. The nanoindentation measurement also shows that Young\u0026rsquo;s modulus for the bulk CPY glass is 6.8 GPa (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ej), which is as high as some reported CP crystals\u003csup\u003e14\u003c/sup\u003e and significantly higher than some natural fiber materials and common polymer materials\u003csup\u003e26\u003c/sup\u003e. In addition, hardness is another important property that can be determined from the indentation response of glass, which quantifies the resistance of glass to permanent deformation. To this end, we determined that the Vickers hardness for CPY glass is 0.32 GPa (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ej), which is superior to polymethyl methacrylate (PMMA) (0.28 GPa)\u003csup\u003e27\u003c/sup\u003e. Collectively, these results compellingly indicate that CPs are robust for forming noncovalent glass with high thermal stability and robust mechanical properties.\u003c/p\u003e \u003cp\u003eThe formation mechanism of CP glass was investigated, with a particular focus on CPY glass as a representative example. To unravel the intermolecular interactions governing glass formation, the FTIR spectra of CPY in both its crystalline and glassy states were obtained (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). In the spectra of CPY crystals, the narrow bands centered at 3304 and 3198 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e are assigned to the O-H and N-H stretching modes, respectively\u003csup\u003e28\u003c/sup\u003e. Additionally, the peaks at 1512, 1468, and 1440 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e correspond to the bending modes of N-H, indicating the existence of predominant hydrogen bonding interactions involving O-H and N-H. Further, combined with the strong peaks at 1666 and 1636 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e in the spectrum of CPY crystal, it can be concluded that CPY crystals are predominantly stabilized by C\u0026thinsp;=\u0026thinsp;O\u0026hellip;H-O and C\u0026thinsp;=\u0026thinsp;O\u0026hellip;H-N hydrogen bonds. Such networks have been confirmed by the hydrogen-bond arrays shown in the single-crystal structure of CPY (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec and Supplementary Figs.\u0026nbsp;6a, b). The two carbonyl oxygens of the diketopiperazine (DPK) ring form hydrogen bonds with the phenolic hydroxyl groups and the N-H group of the DPK ring in the neighbor (referred to as dimer 1 and dimer 2), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed. Furthermore, the well-defined peaks that manifest at 1609, 1591, and 1585 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, originating from the aromatic C\u0026thinsp;=\u0026thinsp;C stretching modes, underscore the ordered aromatic arrangement of aromatic entities within the single-crystal of CPY. The underlying reasons for such aromatic ordering can be bifurcated: Firstly, for the CPY molecule within the lattice, the orientation of the aromatic ring in the tyrosyl residue is folded towards the DKP ring; Secondly, herringbone stacking of aromatic groups between neighboring CPY molecules results in the long-range ordered aromatic packing (Supplementary Figs.\u0026nbsp;6c, d).\u003c/p\u003e \u003cp\u003eIn contrast to the FTIR spectrum of the CPY crystal, the spectrum for CPY glass demonstrates broadened bands in the 3417\u0026thinsp;\u0026minus;\u0026thinsp;3031 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, 1719\u0026thinsp;\u0026minus;\u0026thinsp;1619 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, and 1600\u0026thinsp;\u0026minus;\u0026thinsp;1584 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e regions, suggesting the presence of multiple types of intermolecular interactions including hydrogen bonding and disordered aromatic interactions. This result has been evidenced by the random and irregular hydrogen-bond networks obtained through all-atom molecular dynamics (AAMD) simulation (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee, f), which is advantageous for forming disordered glass. Moreover, a notable red shift in the IR absorption frequencies of O-H and C\u0026thinsp;=\u0026thinsp;O in the glassy state compared to their crystalline counterparts points to the enhanced hydrogen bonding interaction of C\u0026thinsp;=\u0026thinsp;O\u0026hellip;H-O\u003csup\u003e29\u003c/sup\u003e. In contrast, the blue-shifted vibration frequencies of N-H in CPY glass imply a weakened hydrogen bonding interaction of C\u0026thinsp;=\u0026thinsp;O\u0026hellip;H-N (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Diving deeper with AAMD, and it's apparent that the frequency of the former bonds surpasses that of the latter in the post-formation CPY glass state (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ef). Underpinning these findings, the more intense interaction energies and shorter lengths of the C\u0026thinsp;=\u0026thinsp;O\u0026hellip;H-O hydrogen bonds dominate C\u0026thinsp;=\u0026thinsp;O\u0026hellip;H-N \u003csup\u003e28, 30\u003c/sup\u003e. Moreover, the sharp contrast between the broad bands of C-H and aromatic C\u0026thinsp;=\u0026thinsp;C stretching modes in CPY glass and the well-defined peaks in CPY crystals underscores the transformation from ordered to chaotic aromatic configurations (Supplementary Fig.\u0026nbsp;7). A twofold rationale clarifies this transition. Initially, melting the CPY crystal disrupts the relatively weak hydrogen bonds and alters the conformation of CPY, as supported by the breakage of the C\u0026thinsp;=\u0026thinsp;O\u0026hellip;H-N hydrogen bond and unfolding of the CPY conformation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eg). The AAMD simulation results demonstrate that more clusters stabilized by nonlinear and less-ordered hydrogen bonds existed in CPY glass (Supplementary Fig.\u0026nbsp;7), which inhibits directional growth and crystallization. Simultaneously, the high temperature that stabilizes the supercooled liquid facilitates hydrophobic aggregation. This process gives birth to multiple heterogeneous clusters, as validated by the tunable multicolor emission of CPY glass linked to the quantum confined effects (Supplementary Fig.\u0026nbsp;8)\u003csup\u003e13\u003c/sup\u003e. Multiple CPY clusters prevent the easy packing and diffusion of CPY molecules during the cooling process, thus inhibiting crystallization. Together, the pronounced disparities in FTIR features and molecular arrangement modes between CPY crystals and glass underline a pivotal principle: the interruption of long-range and directional intermolecular interactions, coupled with the emergence of less-ordered and nonspecific intermolecular interactions, promotes the formation of heterogeneous clusters and finally noncovalent glasses.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eConsidering the importance of the thermal stability of amorphous materials for practical applications such as electronic and optoelectronic devices, we further explore the T\u003csub\u003eg\u003c/sub\u003e adjustability of CP glasses through modulating peptide structures (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea and Supplementary Fig.\u0026nbsp;9). When comparing with CPY, the introduction of Phe in place of Tyr makes the T\u003csub\u003eg\u003c/sub\u003e of CFP significantly decrease to 20.4 \u0026deg;C. This decline signifies that the absence of phenolic hydroxyl weakens the intermolecular interactions within CFP glass. Conversely, when Pro is replaced by Trp, the T\u003csub\u003eg\u003c/sub\u003e of CWY rises markedly to 114.8 \u0026deg;C. This rise in T\u003csub\u003eg\u003c/sub\u003e stems from the improved aromatic interactions of CWY, as supported by the elevated T\u003csub\u003eg\u003c/sub\u003e of CWW at 117.8 \u0026deg;C. This hypothesis has been validated by the interaction energies (IE) between stabilized CP dimer clusters obtained through density functional theory (DFT) calculations (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). It becomes clear that the absolute IE values for most stable CFP, CPY, and CWY dimer clusters align with their T\u003csub\u003eg\u003c/sub\u003e trends, in which bigger the IE values are, higher their T\u003csub\u003eg\u003c/sub\u003e are. Whereas the CWW dimer cluster exhibits a divergent trend of increased T\u003csub\u003eg\u003c/sub\u003e but with a relatively lower IE value. Such an exception is most likely due to the enhanced aromatic interactions between CWW clusters. Beyond the role of intermolecular interactions in the T\u003csub\u003eg\u003c/sub\u003e of glass, the molecular motion of CP clusters is another factor that cannot be ignored\u003csup\u003e31\u003c/sup\u003e. For CPs with bulkier residues, the translational, rotational, and vibrational motions of CP molecules are more restricted, leading to a higher T\u003csub\u003eg\u003c/sub\u003e. Thus, the T\u003csub\u003eg\u003c/sub\u003e of CP glass can be tailored according to the type and size of CP residues. Notably, T\u003csub\u003eg\u003c/sub\u003e values of CWW and CWY exceed those of previously reported organic glass based on polymers such as commercial polymethyl methacrylate (T\u003csub\u003eg\u003c/sub\u003e = 107.0 \u0026deg;C)\u003csup\u003e32\u003c/sup\u003e, and small molecules such as 1,3-bis-(1-naphthyl)-5-(2-naphthyl) benzene (T\u003csub\u003eg\u003c/sub\u003e = 73.9 \u0026deg;C) and indomethacin (T\u003csub\u003eg\u003c/sub\u003e = 41.9 \u0026deg;C) with exceptional thermodynamic and kinetic stability\u003csup\u003e33\u003c/sup\u003e. The prominent thermostability of CP glass might significantly facilitate its wide-ranging applications in biomedical interfaces, particularly where the stability above human body temperature is paramount.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe evaluate the glass-forming ability (GFA) of CPs through the ratio of T\u003csub\u003eg\u003c/sub\u003e/T\u003csub\u003em\u003c/sub\u003e, which characterizes the crystallization-resistant ability of the supercooled liquid during quenching. According to Kauzmann\u0026rsquo;s 2/3 law, systems with T\u003csub\u003eg\u003c/sub\u003e/T\u003csub\u003em\u003c/sub\u003e values larger than 2/3 are usually regarded as possessing superior GFA\u003csup\u003e34\u003c/sup\u003e. Given that all \u003cem\u003eT\u003c/em\u003e\u003csub\u003erg\u003c/sub\u003e values for the selected CPs surpass this 2/3 benchmark (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec and Supplementary Table\u0026nbsp;1), it suggests that such CPs\u0026rsquo; supercooled liquids are strong glass-formers, which can effectively hinder the crystallization tendency. In addition to T\u003csub\u003eg\u003c/sub\u003e/T\u003csub\u003em\u003c/sub\u003e describing the crystallization-resistant ability of the glass former, another critical parameter involves the heat capacity jump during the glass transition (ΔC\u003csub\u003ep\u003c/sub\u003e), which is inversely correlated with both the glass network connectivity and the number of the topological constraints\u003csup\u003e35\u003c/sup\u003e. It can be found that CPY glass possesses the smallest ΔC\u003csub\u003ep\u003c/sub\u003e, while CWY and CWW glass possess relatively larger ΔC\u003csub\u003ep\u003c/sub\u003e (Supplementary Table\u0026nbsp;1). This variance can be ascribed to the distinctive local structures with different glass network connectivity. Therefore, it is inferred that more discrete molecular cluster structures exist within the CWY and CWW glass. Of particular note is the observation that the order of ΔC\u003csub\u003ep\u003c/sub\u003e values inversely mirrors that of T\u003csub\u003eg\u003c/sub\u003e, suggesting a possible decline in glass network connectivity with increased aromatic interactions.\u003c/p\u003e \u003cp\u003eSubsequently, the thermodynamic fragility of CP glass was calculated based on an empirical correlation between fragility and thermodynamic parameters proposed by Angell et al.\u003csup\u003e36\u003c/sup\u003e, which is linked to the aging behavior and nonexponential relaxation of viscous liquids\u003csup\u003e37\u003c/sup\u003e. In the classification of strong and fragile liquids, liquids considered \"strong\" are those with minimal structural changes around their T\u003csub\u003eg\u003c/sub\u003e\u003csup\u003e38\u003c/sup\u003e. Strong liquids are often characterized by self-reinforcing networks resistant to temperature-induced structural changes. Fragile liquids usually lack directional bonding and often possess either ionic or aromatic attributes\u003csup\u003e39\u003c/sup\u003e. Upon analysis, it can be found that all the m-values of CP glasses are in the range of 90 to 99, signifying their inclination towards forming glasses with relative ductility\u003csup\u003e40\u003c/sup\u003e. These values are close to those of most polymers, some small organic molecules with abundant aromatic groups, and inorganic glass formers with strong ionic interactions\u003csup\u003e41, 42\u003c/sup\u003e. Yet, these values markedly deviate from those of traditional silicate glass-formers, water, and small organic molecules with strong hydrogen bonding interactions\u003csup\u003e41, 43\u0026ndash;45\u003c/sup\u003e. This disparity can be ascribed to the synergy of hydrogen bonds, aromatic interactions, and hydrophobic effects\u003csup\u003e3, 46\u003c/sup\u003e. Notably, the abundant aromatic and hydrophobic interactions are responsible for the relatively higher m-values of CWY and CWW glasses compared to CFP and CPY glasses (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec and Supplementary Table\u0026nbsp;1). This indicates that CP glasses with different fragility can be engineered by precisely modulating the types of amino acids in CPs.\u003c/p\u003e \u003cp\u003eThe above results highlight TYPE I CPs capable of forming stable glass through direct melting-quenching of CP raw powders at heating and cooling rates of 10 \u0026deg;C min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e. Yet, there exists another type of CPs, referred to as TYPE III, that struggles to form stable glass at identical rates, such as Cyclo(-Gly-Pro) (CGP), Cyclo(-Leu-Pro) (CLP), Cyclo(-Pro-Thr) (CPT), and Cyclo(-Phe-Ser) (CFS) with T\u003csub\u003em\u003c/sub\u003e\u0026lt;T\u003csub\u003ed\u003c/sub\u003e (Supplementary Fig.\u0026nbsp;10). Taking these four CPs as an example (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea), pronounced endothermic peaks were observed in the second upscan DSC curves of CGP, CLP, and CFS, indicating that CGP, CLP, and CFS crystals formed rather than glass during the first cooling process. For the second upscan DSC curve of CPT, a glass-transition phenomenon was first observed at T\u003csub\u003eg\u003c/sub\u003e=14.8 \u0026deg;C, followed by two exothermic peaks because of cold crystallization. According to the classification proposed by Trasi et al\u003csup\u003e47\u003c/sup\u003e, this group of unstable CP glass is rather heterogeneous. In principle, any liquid can be solidified into a glass with a sufficiently fast cooling rate. The slowest rate of bypassing crystallization to form glass characterizes how easily a system can be vitrified\u003csup\u003e48\u003c/sup\u003e. Despite our efforts to increase the cooling rate to inhibit the crystallization of CPs, we failed to achieve stable glass for such CPs. For instance, even at a 40 \u0026deg;C min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e cooling rate, obtaining stable CLP glass remained elusive (Supplementary Fig.\u0026nbsp;11). Considering the random molecular arrangement devoid of long-range ordering in stable CP glass, it is supposed that the entropy maximum of the system can facilitate the formation of stable glass. With this rationale, we attempted to melt and quench the mixtures of different CPs to hamper the crystallization of individual CPs. The sequential appearance of glass transition, cold crystallization, and melting in the second upscan DSC curves of mixtures encompassing two or three types of CPs revealed that unstable glass is formed with increased system entropy (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb and c). Further increasing the number of CP types in the mixture, stable glass can be achieved ultimately (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ed). The emergence of individual CPs in the ESI-MS spectrum confirmed that all the CPs are involved in the multicomponent glass (Supplementary Fig.\u0026nbsp;12). Notably, achieving stable glass based on the mixture of multiple CPs is not a coincidence. Such a strategy has been also applied to fabricating glass containing crystallization-favorable CPs with four or more CP species (Supplementary Figs.\u0026nbsp;13\u0026ndash;16). Taken together, the increasing entropy effect resulting from the increasing number of CP components plays a crucial role in achieving stable multicomponent CP glass (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ee).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo understand the role of entropy in glass formation, we calculate the configurational entropy (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(Δ S\\)\u003c/span\u003e\u003c/span\u003e) of different CP mixtures. The individual CPs are considered ideal colloidal spheres to simplify the calculation. When 2 to 6 CPs are mixed at equimolar amounts, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(Δ S\\)\u003c/span\u003e\u003c/span\u003e increases from 0.69\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(R\\)\u003c/span\u003e\u003c/span\u003e to 1.79\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(R\\)\u003c/span\u003e\u003c/span\u003e, where \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(R\\)\u003c/span\u003e\u003c/span\u003e denotes the ideal gas constant. Drawing parallels from the broadened definition of high-entropy alloy (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(Δ S\\)\u003c/span\u003e\u003c/span\u003e\u0026gt;1.36\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(R\\)\u003c/span\u003e\u003c/span\u003e)\u003csup\u003e49\u003c/sup\u003e, we define the glass composed of four or more equimolar CPs as high-entropy CP (HECP) glass, given that their \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(Δ S\\)\u003c/span\u003e\u003c/span\u003e stands at a minimum of 1.39\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(R\\)\u003c/span\u003e\u003c/span\u003e. Such an increase in conformational entropy indicates an increasing degree of disorder in HECP glass consisting of equimolar CPs.\u003c/p\u003e \u003cp\u003eTo decipher the molecular mechanism underlying the formation of HECP glass, we examined the FTIR and Raman spectra of quenched individual CP samples and HECP glass (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ef and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eg). Well-defined peaks characterized by O-H, N-H, C-H, and C\u0026thinsp;=\u0026thinsp;O stretching vibration modes and the sharp profile corresponding to the benzene ring of CFS were observed in the FTIR and Raman spectra of individual quenched CP products. Such observations hint at the presence of directional intermolecular interactions, including specific hydrogen bonding interactions and ordered-stacking interactions, which facilitate the long-range ordered molecular arrangements. In contrast, such characteristic peaks became weaker or even vanished, merging into broader absorption peaks in the vibration spectra of HECP glass. This indicates the disruption of original ordered molecular arrangements and the emergence of a more chaotic molecular packing paradigm fostered by diverse intermolecular interactions among varied CPs. A possible local random molecular packing pattern within HECP glass was depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eh. Such random arrangements promote the generation of heterogeneous CP clusters, as verified by the multicolor fluorescence imaging of the HECP glass (Supplementary Fig.\u0026nbsp;17). The coexistence of multiple CP clusters can effectively increase the configurational entropy of supercooled liquid consisting of CP mixture, which retards molecular diffusion, effectively retarding relaxation, hinder crystallization, and further facilitate the formation of glass with improved thermal stability\u003csup\u003e50\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNotably, when incorporating CPs with good glass-forming ability, stable glass could be achieved even with fewer than four components (Supplementary Figs.\u0026nbsp;18 and 19). More importantly, the entropy-increasing strategy is not limited to typical CPs but also extends to glasses containing thermally labile CPs, such as CFF, CAA, and CGG, which are characterized by severe decomposition before or near the T\u003csub\u003em\u003c/sub\u003e. Two sets of multicomponent CP glass compositions, namely CFF, CFW, CPY, CWY, CWW or CAA, CGG, CPY, CWY, CWW, were successfully fabricated with an equimolar ratio (Supplementary Figs.\u0026nbsp;20 and 21). Impressively, neither of these glass systems exhibited any signs of thermal decomposition. Delving deeper into the T\u003csub\u003eg\u003c/sub\u003e of HECP glass, proline-rich CP mixtures tend to produce glass with a T\u003csub\u003eg\u003c/sub\u003e no more than 40 \u0026deg;C. In comparison, tryptophan-rich CP mixtures facilitate the formation of glass with a T\u003csub\u003eg\u003c/sub\u003e higher than 100 \u0026deg;C (Supplementary Fig.\u0026nbsp;22). Such a distinction demonstrates the potential to craft a spectrum of glasses with variable T\u003csub\u003eg\u003c/sub\u003e values by precisely manipulating the amino acid types of peptides and the number of compositions. Taken together, these multicomponent HECP glasses, especially those with elevated T\u003csub\u003eg\u003c/sub\u003e, are poised to revolutionize fields such as organic light-emitting diode displays, where there is a dire need for operational stability, compositional flexibility, and macroscopic homogeneity\u003csup\u003e51\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe subsequently delved into the effect of high entropy on the mechanical properties of CP glass. For this purpose, we chose three representative glasses, CPY glass, CFF-CPY-CFW-CWY-CWW HECP glass (referred to as CFF-containing HECP glass), and CAA-CGG-CPY-CFW-CWY HECP glass (referred to as CGG-containing HECP glass), for comparison in the following nanoindentation tests. As illustrated by the load-displacement curves, the HECP glass exhibits a shallower indentation depth compared to the individual CPY glass under the load of 450 mN (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea). This evidences a superior resistance to deformation in the HECP glass as opposed to the individual CP glass. Furthermore, the Young's modulus and Vickers hardness of HECP glass are superior to those of individual CPY glass (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb, c) and some natural fibers and commercial polymer materials, but lower than those of commonly used inorganic glasses. These results suggest that HECP glass represents a novel type of glass, bridging the gap between traditional polymer and inorganic glass. Notably, the CGG-containing HECP glass demonstrates the minimum indentation depth while maximum Young's modulus and Vickers hardness. The significant improvement of mechanical properties may be ascribed to the compact and interconnected architecture inherent to HECP glass (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ed). On the one hand, different CPs, due to variations in their amino acid compositions as shown in Supplementary Table\u0026nbsp;2, have disparate sizes. These dimensionally varied CPs inherently favor densely packed configurations, potentially resulting in the sluggish diffusion of CPs. Concurrently, the coexistence of multiple types of CPs augments the diversity of intermolecular interactions, thereby fostering a denser network within HECP glass. Such a promoted network connectivity can be attributed to the decrease in fragility upon mixing\u003csup\u003e52\u003c/sup\u003e. Therefore, the synergistic effect of sluggish diffusion and hyperconnected network architectures is responsible for the overall enhancement in mechanical performances of HECP glass.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe report the fabrication of stable noncovalent glass based on naturally derived CPs by manipulating their conformation complexity of CP clusters. It was discovered that efficient crystallization inhibition, by increasing the conformation entropy of supercooled liquid, is critical to the formation of stable CP glass. In comparison to their singular counterparts, HECP glass, made up of a multitude of CP components, consistently demonstrate an aptitude for resisting both crystallization and thermal decomposition. They also boast improved mechanical attributes due to the synergistic effect of network connectivity, structural diversity, and close packing patterns inherent to HECP glasses. The Young\u0026rsquo;s modulus and Vickers hardness of HECP glass are superior to some naturally biological materials and commercial polymers, yet they remain inferior to the traditional inorganic glass. These unique mechanical characteristics position the HECP glass not just as an addition, but as a revolutionary entrant in the domain of traditional glasses and amorphous materials. This endeavor marks a seminal progress in the quest to conceive noncovalent glasses derived from naturally prevalent CPs, transcending their existing crystalline counterparts, and paving the way for the next-generation biomolecular materials. Taking advantage of the decent pharmacological activities and optoelectronic properties of CPs, it is believed that such avant-garde glasses with stellar thermal stability and mechanical property would significantly spearhead the conceptualization and realization of biorecyclable noncovalent glasses suitable for biomedical devices and wearable smart devices. Beyond pioneering a new class of functional glass, this study sheds light on the quintessential molecular traits characterizing high-entropy noncovalent glasses, representing a landmark discovery in the landscape of amorphous material science.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data are available in the main text or the Supplementary Information. Additional requests can be made to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by National Science Fund for Distinguished Young Scholars of China (No. 22025207), National Natural Science Foundation of China (No. 22172172, 22372174, and 22232006), Youth Innovation Promotion Association of CAS (Grant No. 2022049), China Scholarship Council (CSC, 202104910187), IPE Project for Frontier Basic Research (Grant No. QYJC-2022-011) and Natural Science Foundation of Hebei Province (No. B2020103036 and B2020103025).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX.Y. and C. Y.\u0026nbsp;developed the concept of high-entropy noncovalent glass\u0026nbsp;and designed the experiments.\u0026nbsp;C.Y., W. F., and S. C.\u0026nbsp;performed the experiments.\u0026nbsp;C.Y., W. F.\u0026nbsp;R. X.,\u0026nbsp;and\u0026nbsp;X.\u0026nbsp;Y.\u0026nbsp;analyzed the experimental data.\u0026nbsp;C.Y. and P. Z. designed the theoretical model and performed the simulations.\u0026nbsp;C.Y. and\u0026nbsp;X. Y.\u0026nbsp;wrote the manuscript.\u0026nbsp;All authors discussed the results and commented on the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary information\u0026nbsp;\u003c/strong\u003eThe online version contains supplementary material available at\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ehttps://doi.org/10.1038/sXXXX-XXX-XXXXX-X.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence and requests for materials\u003c/strong\u003e should be addressed to Xuehai Yan.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFrancl, M., Heart of glass. \u003cem\u003eNat. 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Baseline adjustment was first performed using two empty platinum crucibles. Then, TGA measurements were conducted by placing the CP powders in one platinum crucible on the \"S\" side, with an empty crucible placed on the \"R\" side as a reference. The samples were heated from room temperature to 500\u0026nbsp;°C to determine T\u003csub\u003em\u003c/sub\u003e and T\u003csub\u003ed\u003c/sub\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGlass preparation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe preparation of CP glass is as follows: 10 mg CP powder was heated to the temperature above their T\u003csub\u003em\u003c/sub\u003e and maintained for 5 min at this temperature, then quickly cooled to room temperature. All the above operations are performed in a glove box. The CP powders were exchanged in the oxygen-free glove box for two weeks to eliminate the oxygen adsorbed onto the powders.\u003c/p\u003e\n\u003cp\u003eThe preparation of HECP glass is as follows: Different CP powders were mixed in an equimolar ratio and dissolved in HFIP to get a transparent solution. The solution within an open centrifuge tube was placed in a fume hood to dry. Then, the dried powders were moved to the oxygen-free glove box for two weeks to eliminate the oxygen adsorbed. Finally, HECP glasses were prepared through the same procedure as the preparation of individual CP glasses.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDifferential scanning calorimetry\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDSC measurements were carried out with a DSC 1 instrument (Mettler Toledo, Switzerland). The tests were carried out according to the following steps: (1) The individual or mixed CP powders were placed in an Al crucible. (2) The samples were heated from room temperature (T\u003csub\u003e0\u003c/sub\u003e) to a temperature (T\u003csub\u003e1\u003c/sub\u003e) higher than T\u003csub\u003em\u003c/sub\u003e but lower than T\u003csub\u003ed\u003c/sub\u003e to get the supercooled liquids of individual CPs or mixed CPs. (3) Such melted liquids were kept isothermal for 5 min. (4) The above liquids were cooled to a temperature (T\u003csub\u003e2\u003c/sub\u003e) no higher than T\u003csub\u003e0\u003c/sub\u003e, followed by an isothermal procedure at T\u003csub\u003e2\u003c/sub\u003e for 10 min. (5) Finally, the second heating-cooling cycle between T\u003csub\u003e2\u003c/sub\u003e and T\u003csub\u003e1\u003c/sub\u003e was performed. The T\u003csub\u003em\u003c/sub\u003e was extracted from the first heating scan (Upscan1), while the T\u003csub\u003eg\u003c/sub\u003e was extracted from the second heating scan (Upscan2). All the heating and cooling rates were 10 °C min\u003csup\u003e–1\u003c/sup\u003e, except those specified in this work.\u0026nbsp;The values of ΔC\u003csub\u003ep\u003c/sub\u003e were calculated as the difference of heat capacity during glass transition in the second upscan curves.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePXRD measurement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXRD patterns of CP powders and glass were identified by an X-ray diffractometer with a high brightness source Rigaku SmartLab 9kW (Rigaku, Japan) equipped with a Cu filter and a Cu Kα1 radiation source (λ = 1.5406 Å). The samples were placed in clean silicon slices. The measurements were made in a 2θ range of 10°-50° at ambient temperature with a step of 0.01° (2θ) and a scanning rate of 10° min\u003csup\u003e-1\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBright-field and POM imaging\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBright-field and cross-polarized microscopy images were acquired on a BX53 polarized microscope system (Olympus, Japan).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFluorescence spectroscopy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSolid fluorescence spectra of CPY glass were obtained using a FluoroMax+ spectrofluorometer (Horiba, Japan). Excitation and emission bandwidths were 5 nm, respectively. The CPY glass sample was placed between flat and clean quartz sheets with quantitative grooves.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHR-ESI-MS measurement\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHigh-resolution electrospray ionization mass spectra (HR-ESI-MS) of CPY crystal and glass as well as HECP glass were collected by a 9.4T FT-ICR-ESI MS (Bruker). The MS scan range was set from m/z 100 to 600. The samples including the CPY crystal and glass as well as HECP glass were dissolved in ethanol solution.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNMR spectroscopy\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe solution \u003csup\u003e1\u003c/sup\u003eH NMR spectra of CPY crystal and glass samples were recorded at room temperature on a 600-MHz Avance spectrometer equipped with a triple resonance cryogenic probe using a simple 1D pulse sequence (Bruker, Germany). Chemical shifts were referenced to the residual solvent proton signals of DMSO-d6. The obtained spectra were further analyzed with the MestreNova software\u003csup\u003e53\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFT-IR measurement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAttenuated total reflection FT-IR spectra of the CP powders and glasses were measured on a Bruker VERTEX 70v infrared spectrophotometer. Each spectrum was recorded by performing 32 scans between 4000 and 400 cm\u003csup\u003e-1\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUV-Vis-NIR transmittance/absorption measurement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe transmittance and absorption spectra of the CPY glass in the UV-visible region (200–800 nm) were carried out on a SPECORD200 spectrophotometer by positioning the glasses (ca. 2 mm thick) perpendicular to the incident beam.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFluorescence microscope observation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe fluorescence images of CP glasses under the irradiation were taken with an OLYMPUS IX71 fluorescence microscope (Tokyo, Japan).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNanoindentation measurement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe hardness and Young’s modulus of the samples were measured by nanoindenter (Keysight technologie-G200) with a depth of 1\u0026nbsp;mm, each sample was subjected to at least three indentations using a three-sided pyramidal (Berkovich) diamond indenter.\u0026nbsp;Nanoindentation measurements for the comparison of CPY glass with CFF-containing and CGG-containing HECP glass were performed using the maximum load of 450 mN. When the load was reduced to 10% of the maximum load, thermal drift measurements are taken before the indenter is fully retracted. The loading and unloading times were both 10 s.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCalculation of configurational entropy (ΔS\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe configurational entropy ΔS of the entropy-stabilized CPs glass is calculated based on the following equation\u003csup\u003e54\u003c/sup\u003e:\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComputational methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll-atom molecular dynamics (AAMD) simulations were conducted on the Gromacs package (Version 5.1.4)\u003csup\u003e55\u003c/sup\u003e. The CPY molecule was modeled by the general AMBER force field (GAFF)\u003csup\u003e56\u003c/sup\u003e. The molecular electrostatic potential of the CPY was obtained based on the optimized geometry at the HF/6–31g (d) level of theory, which derives the GAFF parameters for subsequent AAMD. The partial charge was computed on the Antechamber package based on the restrained electrostatic potential (RESP) formalism\u003csup\u003e57\u003c/sup\u003e. In this study, AAMD simulations on 144 CPY molecules consisting of 3Í3Í1 CPY lattices were performed. First, the system underwent minimization using the conjugate-gradient algorithm, employing a maximum force tolerance of 200 kJ mol\u003csup\u003e-1\u003c/sup\u003e. To achieve equilibrium of the temperature and volume, 400 ps of a constant–volume, constant–temperature (NVT) simulation and 400 ps of isothermal-isobaric (NPT) simulations were performed. Subsequently, the entire system underwent a heating, maintenance, and cooling process to simulate annealing. The temperature variations during annealing are depicted in fig. S23. The equations of motion were integrated using the leapfrog algorithm with a time step of 2 fs. For temperature control and pressure regulation, the velocity rescale thermostat and the isotropic Parrinello-Rahman barostat were employed, with relaxation times of 0.4 ps and 2.0 ps, respectively. Electrostatic forces were calculated using the particle-mesh Ewald approach, applying a cutoff of 1.0 nm. Additionally, a 1.0 nm cutoff was utilized for van der Waals forces. The LINCS algorithm was employed at each step to preserve bond lengths.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDensity functional theory (DFT) calculations were employed to investigate the intermolecular interactions between CP dimers. The stable geometries of CP monomer and CP dimers were obtained through the optimization of initial conformations using the Gaussian 09 package\u003csup\u003e58\u003c/sup\u003e. Such complexes were optimized in a vacuum at the\u0026nbsp;wB97XD/6-31G (d) level of theory without symmetry constraints. The harmonic vibrational frequency calculations on the optimized geometries were also performed to ensure the structures at local minima. Interaction energies are defined as the difference between the energy of the dimers and the sum of the CP monomers and are corrected with basis set superposition errors (BSSE) via the counterpoise procedure\u003csup\u003e59\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eMolecular diameters of CGG, CAA, CFF, CFW, CPY, CWY, and CWW were calculated based on the Multiwfn 3.8\u003csup\u003e60\u003c/sup\u003e. Such CPs were first optimized at the HF/6–31g (d) level of theory.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Cyclic peptide, noncovalent glass, high-entropy effect, conformation complexity of clusters, mechanical property","lastPublishedDoi":"10.21203/rs.3.rs-3347593/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3347593/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe design and exploration of stable noncovalent glass based on biomolecules are paramount for the sustainable development of human society. Cyclic peptides (CPs) with remarkable structural rigidity and decent resistance to enzymatic degradation can serve as promising glass formers. However, the potent crystallization tendency hinders their potential in glass construction. Herein, we engineered a series of CP glasses with tunable glass transition behaviors by modulating the conformational complexity of CP clusters. The increasing conformational entropy of the supercooled liquid of CPs compared to their crystalline counterparts is fundamental to the formation of CP noncovalent glass. By incorporating multicomponent CPs, the formation of high-entropy CP (HECP) glass is facilitated, which in turn inhibits the crystallization and decomposition of individual CPs. This process ultimately enhances the stability of CP noncovalent glass. Such HECP glass exhibits enhanced mechanical properties compared to individual CP glass due to the promoted connectivity within the glass network. These findings offer a promising paradigm for designing and developing stable noncovalent glass based on naturally derived biomolecules and advancing their application in pharmaceutical formulations and smart materials.\u003c/p\u003e","manuscriptTitle":"Cyclic Peptide High-Entropy Noncovalent Glass","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-09-13 16:13:09","doi":"10.21203/rs.3.rs-3347593/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-nanotechnology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nnano","sideBox":"Learn more about [Nature Nanotechnology](http://www.nature.com/nnano/)","snPcode":"","submissionUrl":"","title":"Nature Nanotechnology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d382caf2-9484-4442-a6ec-b7f630debf0e","owner":[],"postedDate":"September 13th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":24556357,"name":"Physical sciences/Chemistry/Supramolecular chemistry/Supramolecular polymers"},{"id":24556358,"name":"Physical sciences/Materials science/Biomaterials"},{"id":24556359,"name":"Biological sciences/Biotechnology/Nanobiotechnology"}],"tags":[],"updatedAt":"2024-08-27T07:16:10+00:00","versionOfRecord":{"articleIdentity":"rs-3347593","link":"https://doi.org/10.1038/s41565-024-01766-3","journal":{"identity":"nature-nanotechnology","isVorOnly":false,"title":"Nature Nanotechnology"},"publishedOn":"2024-08-26 04:00:00","publishedOnDateReadable":"August 26th, 2024"},"versionCreatedAt":"2023-09-13 16:13:09","video":"","vorDoi":"10.1038/s41565-024-01766-3","vorDoiUrl":"https://doi.org/10.1038/s41565-024-01766-3","workflowStages":[]},"version":"v1","identity":"rs-3347593","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3347593","identity":"rs-3347593","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}