Disorder-Induced Localization in Spliceosomal Conformational Networks for Resolving Plasmodium RNA–Driven Structural Perturbations and Predicting Functional Arrest

Disorder-Induced Localization in Spliceosomal Conformational Networks for Resolving Plasmodium RNA–Driven Structural Perturbations and Predicting Functional Arrest | 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 Research Article Disorder-Induced Localization in Spliceosomal Conformational Networks for Resolving Plasmodium RNA–Driven Structural Perturbations and Predicting Functional Arrest Moses Udoisoh, Chinenye Ukadinma-Okoye, Ogochukwu Augustina Meko, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9449666/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract The spliceosome is a highly dynamic protein-directed metalloribozyme that maintains eukaryotic gene expression through a precisely choreographed sequence of conformational rearrangements. While native splicing relies on the seamless exploration of a vast conformational landscape, recent evidence indicates that Plasmodium falciparum can deliver parasite-derived RNA into host nuclei to disrupt this machinery. However, a rigorous physical mechanism explaining how these localized perturbations trigger global functional arrest has remained elusive. Here, we develop a biophysical framework that demonstrates that spliceosomal dysfunction is driven by a disorder-induced localization transition within the complex's conformational state space. We apply a similarity transformation of the stochastic master equation to map the spliceosome’s kinetic dynamics onto a Hermitian tight-binding Hamiltonian, where parasite-induced energetic perturbations appear as diagonal and off-diagonal disorder. Spectral analysis reveals the emergence of a critical disorder threshold, \(\:{{\Lambda\:}}_{\text{c}\text{r}\text{i}\text{t}}={\sigma\:}_{ϵ}/\stackrel{\prime }{t}\sim\:1\) , marking a transition from a delocalized regime characterized by extended conformational states and efficient sampling to a localized regime defined by confinement and kinetic trapping. Above this threshold, the effective conformational space collapses, leading to a sharp, nonlinear suppression of catalytic accessibility. We derive a scaling law for splicing efficiency, \(\:\eta\:\sim\:\text{e}\text{x}\text{p}(-\alpha\:{{\Lambda\:}}^{2})\) , which quantitatively captures the onset of functional failure. This work shifts the paradigm of molecular pathology from simple biochemical inhibition to a global physical transition governed by Anderson-type localization. These results establish a direct relationship between molecular disorder and biological output, reframing spliceosomal pathology as a disorder-driven phase transition. Beyond its implications for malaria, this framework provides a universal diagnostic toolkit including localization length and inverse participation ratio to assess the resilience of macromolecular machines. Spliceosome dynamics Plasmodium falciparum RNA interference Anderson localization in biomolecular systems Disorder-induced functional arrest Conformational state networks Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 10 May, 2026 Reviewers invited by journal 26 Apr, 2026 Editor assigned by journal 26 Apr, 2026 Submission checks completed at journal 21 Apr, 2026 First submitted to journal 17 Apr, 2026 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-9449666","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":630096428,"identity":"f6e39de5-d72c-4f3b-b938-bc25b4f933e2","order_by":0,"name":"Moses Udoisoh","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYBADxgZmBgZmhgoJCJeHeC1nSNICJJgZ2xgIa9Ftb3/48AfDYdl+dvaHjwvnWcgbHG9gfPC2jSFP3gG7FrMzZ4yNeRgOG89s5jE2nrlNwnDDmQPMhnPbGIoND+DQciOHTZqB4XDihsM8bNK82yQYN9xIADLaGBI3NuDSkv785w+wFvZn0rxzJOw33H/A/hu/lgQzoGdBWhjMpHkbJBI33GBgYwZpmY/D+yC/SPMYpEP8wnNMInnmmcRmyTnngHpxaTne/vDjjwpr2X7+4w8f89TU2fYdP3zww5sym8T5OBwGAQYoPHAcSTAYHMCnBSuQx2vLKBgFo2AUjCAAAC0RWnHUrJp6AAAAAElFTkSuQmCC","orcid":"","institution":"Ignatius Ajuru University of Education","correspondingAuthor":true,"prefix":"","firstName":"Moses","middleName":"","lastName":"Udoisoh","suffix":""},{"id":630096429,"identity":"66bad7ef-d0c6-45f2-84d7-77bc64839605","order_by":1,"name":"Chinenye Ukadinma-Okoye","email":"","orcid":"","institution":"Nnamdi Azikiwe University","correspondingAuthor":false,"prefix":"","firstName":"Chinenye","middleName":"","lastName":"Ukadinma-Okoye","suffix":""},{"id":630096430,"identity":"e154197a-2483-48ab-a981-07be56bd3f7e","order_by":2,"name":"Ogochukwu Augustina Meko","email":"","orcid":"","institution":"Chukwuemeka Odumegwu Ojukwu university","correspondingAuthor":false,"prefix":"","firstName":"Ogochukwu","middleName":"Augustina","lastName":"Meko","suffix":""},{"id":630096431,"identity":"5e232e93-f56d-4dc6-85e1-142eb0e19606","order_by":3,"name":"Ediomo Mandu Ekanem","email":"","orcid":"","institution":"Abia state university","correspondingAuthor":false,"prefix":"","firstName":"Ediomo","middleName":"Mandu","lastName":"Ekanem","suffix":""}],"badges":[],"createdAt":"2026-04-17 13:23:51","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9449666/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9449666/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108534246,"identity":"e4e05b31-80b8-46b7-b421-01730c47da13","added_by":"auto","created_at":"2026-05-05 16:40:21","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1027976,"visible":true,"origin":"","legend":"","description":"","filename":"DisorderInducedLocalizationinSpliceosomalConformationalNetworksforResolvingPlasmodiumRNADrivenStructuralPerturbationsandPredictingFunctionalArrestcompleted.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9449666/v1_covered_dafd8ed2-20bd-492b-9b75-5052cddc875c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Disorder-Induced Localization in Spliceosomal Conformational Networks for Resolving Plasmodium RNA–Driven Structural Perturbations and Predicting Functional Arrest","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-biological-physics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jobp","sideBox":"Learn more about [Journal of Biological Physics](http://link.springer.com/journal/10867)","snPcode":"10867","submissionUrl":"https://submission.nature.com/new-submission/10867/3","title":"Journal of Biological Physics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Spliceosome dynamics, Plasmodium falciparum RNA interference, Anderson localization in biomolecular systems, Disorder-induced functional arrest, Conformational state networks","lastPublishedDoi":"10.21203/rs.3.rs-9449666/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9449666/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe spliceosome is a highly dynamic protein-directed metalloribozyme that maintains eukaryotic gene expression through a precisely choreographed sequence of conformational rearrangements. While native splicing relies on the seamless exploration of a vast conformational landscape, recent evidence indicates that \u003cem\u003ePlasmodium falciparum\u003c/em\u003e can deliver parasite-derived RNA into host nuclei to disrupt this machinery. However, a rigorous physical mechanism explaining how these localized perturbations trigger global functional arrest has remained elusive. Here, we develop a biophysical framework that demonstrates that spliceosomal dysfunction is driven by a disorder-induced localization transition within the complex's conformational state space. We apply a similarity transformation of the stochastic master equation to map the spliceosome\u0026rsquo;s kinetic dynamics onto a Hermitian tight-binding Hamiltonian, where parasite-induced energetic perturbations appear as diagonal and off-diagonal disorder. Spectral analysis reveals the emergence of a critical disorder threshold, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{{\\Lambda\\:}}_{\\text{c}\\text{r}\\text{i}\\text{t}}={\\sigma\\:}_{ϵ}/\\stackrel{\\prime }{t}\\sim\\:1\\)\u003c/span\u003e\u003c/span\u003e, marking a transition from a delocalized regime characterized by extended conformational states and efficient sampling to a localized regime defined by confinement and kinetic trapping. Above this threshold, the effective conformational space collapses, leading to a sharp, nonlinear suppression of catalytic accessibility. We derive a scaling law for splicing efficiency, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\eta\\:\\sim\\:\\text{e}\\text{x}\\text{p}(-\\alpha\\:{{\\Lambda\\:}}^{2})\\)\u003c/span\u003e\u003c/span\u003e, which quantitatively captures the onset of functional failure. This work shifts the paradigm of molecular pathology from simple biochemical inhibition to a global physical transition governed by Anderson-type localization. These results establish a direct relationship between molecular disorder and biological output, reframing spliceosomal pathology as a disorder-driven phase transition. Beyond its implications for malaria, this framework provides a universal diagnostic toolkit including localization length and inverse participation ratio to assess the resilience of macromolecular machines.\u003c/p\u003e","manuscriptTitle":"Disorder-Induced Localization in Spliceosomal Conformational Networks for Resolving Plasmodium RNA–Driven Structural Perturbations and Predicting Functional Arrest","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-05 16:38:58","doi":"10.21203/rs.3.rs-9449666/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"304470275896989012950905706570527548680","date":"2026-05-10T07:19:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-26T23:20:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-26T20:43:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-21T04:38:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Biological Physics","date":"2026-04-17T13:19:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-biological-physics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jobp","sideBox":"Learn more about [Journal of Biological Physics](http://link.springer.com/journal/10867)","snPcode":"10867","submissionUrl":"https://submission.nature.com/new-submission/10867/3","title":"Journal of Biological Physics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d9561c92-734c-4e5d-af0d-ea1b9bac8d1d","owner":[],"postedDate":"May 5th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"304470275896989012950905706570527548680","date":"2026-05-10T07:19:10+00:00","index":29,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-05T16:38:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-05 16:38:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9449666","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9449666","identity":"rs-9449666","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}