Toward Improved Description of DNA Backbone: Revisiting Epsilon and Zeta Torsion Force Field Parameters

Abstract

We present a refinement of the backbone torsion parameters ε and ζ of the Cornell et al. AMBER force field for DNA simulations. The new parameters, denoted as εζOL1, were derived from quantum-mechanical calculations with inclusion of conformation-dependent solvation effects according to the recently reported methodology (J. Chem. Theory Comput. 2012, 7(9), 2886-2902). The performance of the refined parameters was analyzed by means of extended molecular dynamics (MD) simulations for several representative systems. The results showed that the εζOL1 refinement improves the backbone description of B-DNA double helices and G-DNA stem. In B-DNA simulations, we observed an average increase of the helical twist and narrowing of the major groove, thus achieving better agreement with X-ray and solution NMR data. The balance between populations of BI and BII backbone substates was shifted towards the BII state, in better agreement with ensemble-refined solution experimental results. Furthermore, the refined parameters decreased the backbone RMS deviations in B-DNA MD simulations. In the antiparallel guanine quadruplex (G-DNA) the εζOL1 modification improved the description of non-canonical α/γ backbone substates, which were shown to be coupled to the ε/ζ torsion potential. Thus, the refinement is suggested as a possible alternative to the current ε/ζ torsion potential, which may enable more accurate modeling of nucleic acids. However, long-term testing is recommended before its routine application in DNA simulations.

Triplex intermediates in folding of human telomeric quadruplexes probed by microsecond-scale molecular dynamics simulations

“…Parmc OL4 improves the shape of the syn region of the c torsional potential of the force field and affects the balance and kinetics between the syn and anti c regions [78]. We tested also addition of the 2013 parmεz OL1 modification, which refines the ε/z torsion potentials, improving indirectly also balance of the noncanonical a/g backbone substates in G-DNA [79] (Table 1, Supporting Table SI). The later modifications are not essential to achieve a basic stability of DNA simulations and are still under testing.…”

Multiscale simulation of DNA

“…This has encouraged further refinements, which are becoming now available to the community. For example, the Czech group has introduced specific corrections to improve sampling around  and  degrees of freedom [42,43]. In parallel, MacK ll's group has developed an updated version of the CHARMM force field (CHARMM36), which corrected several inaccuracies of previous releases of this family of force-fields [45].…”

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.…”

“…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.…”