Refinement of the Sugar–Phosphate Backbone Torsion Beta for AMBER Force Fields Improves the Description of Z- and B-DNA

Abstract

Z-DNA duplexes are a particularly complicated test case for current force fields. We performed a set of explicit solvent molecular dynamics (MD) simulations with various AMBER force field parametrizations including our recent refinements of the ε/ζ and glycosidic torsions. None of these force fields described the ZI/ZII and other backbone substates correctly, and all of them underpredicted the population of the important ZI substate. We show that this underprediction can be attributed to an inaccurate potential for the sugar-phosphate backbone torsion angle β. We suggest a refinement of this potential, β(OL1), which was derived using our recently introduced methodology that includes conformation-dependent solvation effects. The new potential significantly increases the stability of the dominant ZI backbone substate and improves the overall description of the Z-DNA backbone. It also has a positive (albeit small) impact on another important DNA form, the antiparallel guanine quadruplex (G-DNA), and improves the description of the canonical B-DNA backbone by increasing the population of BII backbone substates, providing a better agreement with experiment. We recommend using β(OL1) in combination with our previously introduced corrections, εζ(OL1) and χ(OL4), (the combination being named OL15) as a possible alternative to the current β torsion potential for more accurate modeling of nucleic acids.

A DNA structural alphabet provides new insight into DNA flexibility

“…Despite detailed discussion of this topic being outside the scope of this study, we conclude that the force fields optimized for long MD simulations of DNA do reproduce the main D-Dd structural features quite realistically. The closest match between the distribution of NtC in crystal structures and MD simulations is observed in short 100 ns simulations (Č erný et al, 2008) and long 1 ms simulations (Galindo-Murillo et al, 2016) with the bsc0 force field (Pé rez et al, 2007); the bsc1 force field (Ivani et al, 2016) and OL15 (Zgarbová et al, 2015) force field underestimate the frequency of B/A forms (AB01, BA06) and overemphasize that of BII (BB07).…”

The temperature dependence of the helical twist of DNA

“…However, the underlying free energy profile is a result of a large number of interatomic interactions involving not only DNA but also the surrounding water molecules and ions. In MD simulations, these interactions are captured by atomistic force fields, which are under constant development, with major updates released recently (39,40). To analyze the response of twist to temperature at atomic resolution, we performed a series of ∼μs, atomic resolution, explicit solvent MD simulations of a mixed 33 bp DNA sequence at temperatures ranging from 7°C to 47°C using the OL15 Amber force field (39).…”

Computational Methods to Study G-Quadruplex–Ligand Complexes

“…The Czech group led by Jurecka introduced the OL15 force field. 78 They have made similar improvements to the parmbsc0 force field with refinements in the χ 79 , ε/ζ 80 and β torsion angles. 78 A subsequent report by Sponer group to study loop conformations in parallel-stranded quadruplexes highlighted the limitations of these force fields to accurately reproduce experimental structure in all these force field versions.…”

“…78 They have made similar improvements to the parmbsc0 force field with refinements in the χ 79 , ε/ζ 80 and β torsion angles. 78 A subsequent report by Sponer group to study loop conformations in parallel-stranded quadruplexes highlighted the limitations of these force fields to accurately reproduce experimental structure in all these force field versions. 81 However, it is worth mentioning that modifications of the AMBER force field to bsc0, bsc1 and OL15 were developed to improve the accuracy of simulating double-stranded DNA.…”

“…This is not handled by the non-polarizable atom-atom pair-additive force field. The current force fields like parmbsc0 73 , parmbsc1 77 and OL15 78,80 have introduced several correction terms for the DNA backbone profile, which have been able to keep the fluctuations within acceptable limits over the entire course of nano-or microscale simulations.…”