Molecular dynamics (MD) simulations became a leading tool for investigation of structural dynamics of nucleic acids. Despite recent efforts to improve the empirical potentials (force fields, ffs), RNA ffs have persisting deficiencies, which hamper their utilization in quantitatively accurate simulations. Previous studies have shown that at least two salient problems contribute to difficulties in the description of free-energy landscapes of small RNA motifs: (i) excessive stabilization of the unfolded single-stranded RNA ensemble by intramolecular base-phosphate and sugar-phosphate interactions and (ii) destabilization of the native folded state by underestimation of stability of base pairing. Here, we introduce a general ff term (gHBfix) that can selectively fine-tune nonbonding interaction terms in RNA ffs, in particular, the H bonds. The gHBfix potential affects the pairwise interactions between all possible pairs of the specific atom types, while all other interactions remain intact; i.e., it is not a structure-based model. In order to probe the ability of the gHBfix potential to refine the ff nonbonded terms, we performed an extensive set of folding simulations of RNA tetranucleotides and tetraloops. On the basis of these data, we propose particular gHBfix parameters to modify the AMBER RNA ff. The suggested parametrization significantly improves the agreement between experimental data and the simulation conformational ensembles, although our current ff version still remains far from being flawless. While attempts to tune the RNA ffs by conventional reparametrizations of dihedral potentials or nonbonded terms can lead to major undesired side effects, as we demonstrate for some recently published ffs, gHBfix has a clear promising potential to improve the ff performance while avoiding introduction of major new imbalances.

Department of Physical Chemistry Faculty of Science Palacký University tř 17 listopadu 12 771 46 Olomouc Czech Republic

Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 612 65 Brno Czech Republic

Laboratory of Chemical Physics National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda Maryland 20892 0520 United States

Regional Centre of Advanced Technologies and Materials Faculty of Science Palacký University tř 17 listopadu 12 771 46 Olomouc Czech Republic

Scuola Internazionale Superiore di Studi Avanzati SISSA via Bonomea 265 34136 Trieste Italy

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J Chem Theory Comput. 2020 Jan 14;16(1):818-819. doi: 10.1021/acs.jctc.9b01189. PubMed

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