Implicit Electronic Polarization via Charge Scaling in Amber OLx Nucleic Acid Force Fields Improves Ion Pairing...

While divalent ions are known to be involved in key biological processes such as RNA folding or DNA-histone interactions, these interactions are poorly captured in molecular dynamics simulations with empirical force fields, which suffer from strong overbinding artifacts. Hence, there is a strong need for improved descriptions of (divalent) ions in nucleic acid simulations. In this work, we explore the possibility to improve ion-binding properties of the popular Amber-OL15 force field using the Electronic Continuum Correction (ECC) approach, which includes electronic polarization through charge scaling, limited here to the phosphate backbone. This strategy yields very promising results, with essentially no degradation of the conformational properties of selected DNA (and a ds-RNA) sequences and a strong improvement of both monovalent ion retention in G-quadruplexes and divalent ion pairing. As the ECC modification appears mostly orthogonal to force field refinements focused on backbone dihedral parameters, this work suggests a systematic way to improve the ion pairing properties of nucleic acids in all-atom MD simulations.