Exploring Conformational Transitions of RNA Dimers via Machine Learning Potentials

Leonardo Medrano Sandonas, Macarena Tolmos Nehme, Luis Fernando Cofas-Vargas, Gustavo E. Olivos-Ramirez, Gianaurelio Cuniberti, Simón Poblete, Adolfo B. Poma
2026 · doi:10.64898/2026.02.25.707885
preprint OA: closed CC-BY-ND-4.0
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Abstract

ABSTRACT RNA is a flexible biopolymer that adopts diverse conformations while forming structural motifs essential for its function. Classical RNA force fields often show limited transferability and inefficient sampling of transitions between stable states, particularly in moderately large RNA. To address these limitations, quantum-informed machine learning (ML) potentials have recently emerged as a promising alternative, offering improved accuracy and transferability relative to classical force fields. Here, we assess ML potentials for exploring RNA conformations using the adenine–adenine dinucleoside monophosphate (ApA) dimer, a fundamental RNA building block. We generated an extensive quantum-mechanical (QM) dataset for ApA conformations obtained from temperature replica exchange molecular dynamics (TREMD) simulations. Despite its small size, the ApA dimer exhibits six conformations in which quantum effects and solvent-mediated interactions play crucial roles. Using this dataset, we parameterized ML potentials based on the equivariant MACE architecture and informed by both ab-initio and semi-empirical data. The resulting potentials reproduce key conformational features of the ApA system, including base stacking, sugar puckering, and backbone flexibility, and provide broader coverage of structural transitions than the general-purpose SO3LR and MACE-OFF24 models. These findings highlight the importance of quantum-accurate RNA force fields towards the structural and energetic characterization of RNA complexes.
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ABSTRACT RNA is a flexible biopolymer that adopts diverse conformations while forming structural motifs essential for its function. Classical RNA force fields often show limited transferability and inefficient sampling of transitions between stable states, particularly in moderately large RNA. To address these limitations, quantum-informed machine learning (ML) potentials have recently emerged as a promising alternative, offering improved accuracy and transferability relative to classical force fields. Here, we assess ML potentials for exploring RNA conformations using the adenine–adenine dinucleoside monophosphate (ApA) dimer, a fundamental RNA building block. We generated an extensive quantum-mechanical (QM) dataset for ApA conformations obtained from temperature replica exchange molecular dynamics (TREMD) simulations. Despite its small size, the ApA dimer exhibits six conformations in which quantum effects and solvent-mediated interactions play crucial roles. Using this dataset, we parameterized ML potentials based on the equivariant MACE architecture and informed by both ab-initio and semi-empirical data. The resulting potentials reproduce key conformational features of the ApA system, including base stacking, sugar puckering, and backbone flexibility, and provide broader coverage of structural transitions than the general-purpose SO3LR and MACE-OFF24 models. These findings highlight the importance of quantum-accurate RNA force fields towards the structural and energetic characterization of RNA complexes. Competing Interest Statement The authors have declared no competing interest.

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[{'doi': '10.13039/501100001659', 'name': 'Deutsche Forschungsgemeinschaft', 'awards': ['390696704']}, {'doi': '10.13039/501100001659', 'name': 'Deutsche Forschungsgemeinschaft', 'awards': ['EXC 3035']}, {'doi': '10.13039/501100001659', 'name': 'Deutsche Forschungsgemeinschaft', 'awards': ['533767731']}, {'doi': None, 'name': 'Fondecyt, Chile', 'awards': ['1231071']}, {'doi': None, 'name': 'National Science Center, Poland', 'awards': ['2022/45/B/NZ1/02519']}]

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License: CC-BY-ND-4.0