Molecular Dynamics Simulations for RNA—Benchmark and Folding-Stretching Experiments

The ability to accurately model RNA in computer simulations is important as potential applications are increasing with the mRNA vaccine platform. Various length and shape of RNA chains as well as their interactions with the environment, play an important role in medicine, origin of life and homochirality studies. The extensive experimental research on short RNA strings provide an excellent opportunity to utilize those structures as benchmarks for nucleic acids force-fields[1], and increase our understanding of structural and dynamic properties RNA strings. In recent years, <i>all-atom</i> molecular dynamics was used to show accurate RNA folding[2], dynamic protein-RNA binding[3] and plasticity of dsRNA duplexes[4] among others.<br/>We have studied a series of RNA dinucleotides, tetranucleotides and hairpin loops, GAGA (IZIG) and UUCG (2KOC), with respect to structural stability in vacuum, and in presence of implicit- and explicit water, for AMBER-OL3, OPLS-AA/M, and CHARM-36. The results of J3 coefficients from dihedral angles were compared with experimental NMR data. For these models, AMBER recreated the structures with best agreement with experimental data, compared to OPLS and CHARMM. Based on results stretching-folding experiments were conducted on selected nucleotides in AMBER-OL3/bsc0 force field with explicit water and vacuum. The dynamic and mechanical properties of RNA chains were shown as a function of chain length and investigated further for size effects.<br/><br/>[1] J. Zhao et al. “Nuclear Magnetic Resonance of Single-Stranded RNAs and DNAs of CAAU and UCAAUC as Benchmarks for Molecular Dynamics Simulations”. In: J. Chem. Theory Comput. 16.3 (2020), pp. 1968–1984. doi:10.1021/acs.jctc.9b00912.<br/>[2] A. M. Yu et al. “Computationally reconstructing co-transcriptional RNA folding from experimental data reveals rearrangement of non-native folding intermediates”. In: Nat. Comput. Sci. 81.4 (2021), pp. 870–883. doi:10.1016/j.molcel.2020.12.017.<br/>[3] M. Krepl et al. “MD simulations reveal the basis for dynamic assembly of Hfq RNA complexes”. In: J. Biol. Chem. 296.100656 (2021), pp. 1–15. doi:10.1016/j.jbc.2021.100656.<br/>[4] W. He et al. “The structural plasticity of nucleic acid duplexes revealed by WAXS and MD”. In: Sci. Adc. 7.17 (2021), pp. 1–15. doi:10.11126/sciadv.abf6106.