Free Energy-Based Refinement of DNA Force Field via Modification of Multiple Nonbonding Energy Terms

The amber-OL21 force field (ff) was developed to better describe noncanonical DNA, including Z-DNA. Despite its improvements for DNA simulations, this study found that OL21's scope of application was limited by embedded ff artifacts. In a benchmark set of seven DNA molecules, including two double-stranded DNAs transitioning between B- and Z-DNA and five single-stranded DNAs folding into mini-dumbbell or G-quadruplex structures, the free energy landscapes obtained using OL21 revealed several issues: Z-DNA was overly stabilized; misfolded states in mini-dumbbell DNAs were most stable; DNA GQ folding was consistently biased toward an antiparallel topology. To address these issues, a simple van der Waals (vdW) correction scheme, referred to as vdW5, was proposed for OL21. This involved revising multiple nonbonding energy terms to improve the overall quality of the free energy landscapes. The vdW5 correction effectively eliminated the artifacts in OL21, providing significantly improved free energy representations for DNAs tested. The vdW5-level revision substantially enhanced the predictive power of DNA simulations, thereby extending the scope of application for amber-OL21.