Improving the Performance of the Amber RNA Force Field by Tuning the Hydrogen-Bonding Interactions

Abstract

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.

Surviving the deluge of biosimulation data

“…The recent progress in MD simulations, with improvements in reliability, size of the systems under study, and timescale, is based on three pillars: The continuous development of force fields , which are approaching the capability to reproduce many experimental observables for nucleic acids and proteins, including those without well‐defined structure . Recent force fields allow for the reaching of larger timescales, opening the possibility to explore long conformational transitions such as folding, or allosteric changes.…”

UNCG RNA tetraloop as a formidable force-field challenge for MD simulations

“…Recent folding simulations of the UNCG TL indicated a large free-energy imbalance between native (folded) and other states (misfolded/unfolded conformations). [6][7][8][9][10][17][18][19][20] In addition, the characteristic UNCG native structure is lost in sufficiently long standard simulations. Two different effects were deemed to dominantly lead to the incorrect folded/unfolded free-energy balance, namely, (i) excessive stabilization of the unfolded ssRNA structure by intramolecular base-phosphate and sugar-phosphate interactions and (ii) destabilization of the native folded state by underestimation of the native H-bonds including the stem base pairing.…”

“…Two different effects were deemed to dominantly lead to the incorrect folded/unfolded free-energy balance, namely, (i) excessive stabilization of the unfolded ssRNA structure by intramolecular base-phosphate and sugar-phosphate interactions and (ii) destabilization of the native folded state by underestimation of the native H-bonds including the stem base pairing. 8,9,21,22 Recently, we introduced a general external potential tuning H-bond interactions (gHBfix), 8,19 which is used as an additional ff term to improve RNA simulations. Even with this modification, description of the UNCG TL remained imbalanced and we were not capable to fold the 8-mer TL.…”

“…4), we are not aware of any existing RNA ff able to properly describe UNCG TL with all its signature interactions. 19,23 Some success has been recently achieved with the DESRES ff with specific ion parameters using the UNCG 14-mer with longer A-RNA stem. 24 However, the same ff leads to a complete disruption (including secondary structure rearrangements) of some other important RNA systems even in standard simulations on sub-microsecond timescale.…”

“…24 However, the same ff leads to a complete disruption (including secondary structure rearrangements) of some other important RNA systems even in standard simulations on sub-microsecond timescale. 19,23 Such side-effects in simulations of functional RNA molecules outweigh partial improvements for small models. 19,23 Thus, the UNCG ff issue remains unresolved.…”