Toward Force Fields with Improved Base Stacking Descriptions.

Recent DNA force fields indicate good performance in describing flexibility and structural stability of double-stranded B-DNA. However, it is not clear how accurately base stacking interactions are represented that are critical for simulating structure formation processes and conformational changes. Based on the equilibrium nucleoside association and base pair nicking, we find that the recent Tumuc1 force field improves the description of base stacking compared to previous state-of-the-art force fields. Nevertheless, base pair stacking is still overstabilized compared to experiment. We propose a rapid method to reweight calculated free energies of stacking upon force field modifications in order to generate improved parameters. A decrease of the Lennard-Jones attraction between nucleo-bases alone appears insufficient; however, adjustments in the partial charge distribution on base atoms could help to further improve the force field description of base stacking.