B–Z DNA Transitions under Z–DNA-Favoring Conditions: Benchmarking the OL21-vdW7 Force Field

The B-Z DNA transition provides a rigorous benchmark for all-atom DNA force fields because it arises from a finely balanced free-energy competition between conformational states with distinct backbone geometries, sugar-pucker preferences, ion organization, and hydration patterns. Using enhanced-sampling molecular dynamics simulations in the NPT ensemble over a broad pressure range, we show that the recently modified OL21-vdW7 force field correctly describes the thermodynamic preference between B-DNA and Z-DNA under multiple Z-DNA-stabilizing conditions, including elevated pressure, high salt concentration, and multivalent polycations. The resulting two-dimensional free-energy landscapes resolve the plausible transition pathway and quantify the associated thermodynamic and structural responses. In addition to reproducing established experimental stabilization trends, OL21-vdW7 yields a cooperative nucleation-propagation mechanism initiated by the formation of a minimal Z-DNA segment and a single B-Z junction. The pressure dependence of the transition reflects a negative volume change, whose magnitude is largest under low-salt conditions. Overall, these results demonstrate the transferability of OL21-vdW7 for duplex DNA and highlight B-Z transitions as a stringent test case for force-field development and validation.