van der Waals Parameter Scanning with Amber Nucleic Acid Force Fields: Revisiting Means to Better Capture the RNA/DNA Structure through MD

Abstract

Molecular dynamics simulations can be used in combination with experimental techniques to uncover the intricacies of biomolecular structure, dynamics, and the resulting interactions. However, many noncanonical nucleic acid structures have proven to be challenging to replicate in accurate agreement with experimental data, often attributed to known force field deficiencies. A common force field criticism is the handling of van der Waals (vdW) parameters, which have not been updated since the regular use of Ewald's methods became routine. This work dives into the effects of minute vdW radii shifts on RNA tetranucleotide, B-DNA, and Z-DNA model systems described by commonly used Amber force fields. Using multidimensional replica exchange molecular dynamics (M-REMD), the GACC RNA tetranucleotide demonstrated changes in the structural distribution between the NMR minor and anomalous structure populations based on the O2′ vdW radii scanning. However, no significant change in the NMR Major conformation population was observed. There were minimal changes in the B-DNA structure but there were more substantial improvements in Z-DNA structural descriptions, specifically with the Tumuc1 force field. This occurred with both LJbb vdW radii adjustments and incorporation of the CUFIX nonbonded parameter modifications. Though the limited vdW modifications tested did not provide a universal fix to the challenge of simulating the various known nucleic acid structures, they do provide direction and a greater understanding for future force field development efforts.

Accurately Modeling RNA Stem-Loops in an Implicit Solvent Environment

“…When the simulations are clustered employing non-hydrogenic atoms of the loop and closing base pair residues (Figure ), the RMSD values from the NMR structure were relatively large, with most in the 4–7 Å range. This is not a surprising result, as in explicit solvent with a buffer of ions, it is quite difficult to accurately model RNA loop structures. − Notably, two loop structures (1I46 and 1JTW) generally exhibited smaller RMSD values of 2.5 and 2.4 Å, respectively, indicating that the loop and first base pair residues are qualitatively close to the experimental structure. In both structures, the bases are on the correct side of the loop, and there are no appreciable distortions in the backbones.…”