Development of Force Field Parameters for the Simulation of Single- and Double-Stranded DNA Molecules and DNA-Protein Complexes.

Although molecular dynamics (MD) simulations have been used extensively to study the structural dynamics of proteins, the role of MD simulation in studies of nucleic acid based systems has been more limited. One contributing factor to this disparity is the historically lower level of accuracy of the physical models used in such simulations to describe interactions involving nucleic acids. By modifying nonbonded and torsion parameters of a force field from the Amber family of models, we recently developed force field parameters for RNA that achieve a level of accuracy comparable to that of state-of-the-art protein force fields. Here we report force field parameters for DNA, which we developed by transferring nonbonded parameters from our recently reported RNA force field and making subsequent adjustments to torsion parameters. We have also modified the backbone charges in both the RNA and DNA parameter sets to make the treatment of electrostatics compatible with our recently developed variant of the Amber protein and ion force field. We name the force field resulting from the union of these three parameter sets (the new DNA parameters, the revised RNA parameters, and the existing protein and ion parameters) . Extensive testing of DES-Amber indicates that it can describe the thermal stability and conformational flexibility of single- and double-stranded DNA systems with a level of accuracy comparable to or, especially for disordered systems, exceeding that of state-of-the-art nucleic acid force fields. Finally, we show that, in certain favorable cases, DES-Amber can be used for long-timescale simulations of protein-nucleic acid complexes.