Structural Convergence of MD simulations on RNA Motifs: A tRNA case study
- 1Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive West, Lethbridge, AB, Canada, T1K 3M4
- 2Department of Chemistry, University of Manitoba, 66 Chancellors Circle, Winnipeg, MB, R3T 2N2
Abstract
A detailed understanding of the structural dynamics of diverse RNA architectures is critical for elucidating the chemical basis of cellular function and expanding the use of RNA in medicine and biotechnology. While classical molecular dynamics (MD) simulations can provide this much-needed atomic information, sampling requirements remain poorly characterized for RNA systems. In the present study, we compared the conformational ensemble sampled by five independent 5 μs trajectories and 60 independent 500 ns replicas for unmodified Escherichia coli tRNAPhe under three (monovalent, crystallographic-Mg2+, and 6 Mg2+) environmental conditions, yielding 165 μs of aggregate sampling. Although the global L-shaped tRNA fold was retained across all simulations, structural convergence was strongly motif-dependent. Mean base-pair and base-step descriptors of the rigid acceptor and anticodon stem-loop duplex regions were reproduced with modest replication across metal environments. In contrast, the dynamic anticodon loop exhibited substantial trajectory-to-trajectory heterogeneity. A stacking-based analysis identified diverse loop conformations with counterparts in experimentally determined tRNA structures, showing that ensembles of independent classical MD replicas can sample diverse experimentally observed conformations without enhanced sampling. While fewer long trajectories incompletely sampled the heterogeneous loop conformational space, ensembles of many shorter replicas are key to exploring the conformational dynamics of RNA motifs like hairpins. Inclusion of Mg2+ also shifted the sampled conformational ensemble, underscoring the importance of mimicking the experimentally-relevant ionic environment. Overall, our findings offer practical guidelines for MD simulation setup, including trajectory length, replica number, and divalent ion conditions, for studies of RNA systems featuring similar tertiary architectures.
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BibTeX
@misc{pounder2026structural,
title = {{Structural Convergence of MD simulations on RNA Motifs: A tRNA case study}},
author = {Austin Pounder and Mark J. Lea and Umer Yaqoob and Zaki Olvis and Cynthia Fonderson and Ute Kothe and Stacey D. Wetmore},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010140/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010140/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Structural Convergence of MD simulations on RNA Motifs: A tRNA case study
AU - Austin Pounder
AU - Mark J. Lea
AU - Umer Yaqoob
AU - Zaki Olvis
AU - Cynthia Fonderson
AU - Ute Kothe
AU - Stacey D. Wetmore
PY - 2026
DA - 2026/10/09
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010140/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010140/v1
AB - A detailed understanding of the structural dynamics of diverse RNA architectures is critical for elucidating the chemical basis of cellular function and expanding the use of RNA in medicine and biotechnology. While classical molecular dynamics (MD) simulations can provide this much-needed atomic information, sampling requirements remain poorly characterized for RNA systems. In the present study, we compared the conformational ensemble sampled by five independent 5 μs trajectories and 60 independent 500 ns replicas for unmodified Escherichia coli tRNAPhe under three (monovalent, crystallographic-Mg2+, and 6 Mg2+) environmental conditions, yielding 165 μs of aggregate sampling. Although the global L-shaped tRNA fold was retained across all simulations, structural convergence was strongly motif-dependent. Mean base-pair and base-step descriptors of the rigid acceptor and anticodon stem-loop duplex regions were reproduced with modest replication across metal environments. In contrast, the dynamic anticodon loop exhibited substantial trajectory-to-trajectory heterogeneity. A stacking-based analysis identified diverse loop conformations with counterparts in experimentally determined tRNA structures, showing that ensembles of independent classical MD replicas can sample diverse experimentally observed conformations without enhanced sampling. While fewer long trajectories incompletely sampled the heterogeneous loop conformational space, ensembles of many shorter replicas are key to exploring the conformational dynamics of RNA motifs like hairpins. Inclusion of Mg2+ also shifted the sampled conformational ensemble, underscoring the importance of mimicking the experimentally-relevant ionic environment. Overall, our findings offer practical guidelines for MD simulation setup, including trajectory length, replica number, and divalent ion conditions, for studies of RNA systems featuring similar tertiary architectures.
ER -