Molecular dynamic simulations of environment and sequence dependent DNA conformations: The development of the BMS nucleic acid force field and comparison with experimental results

Molecular dynamic (MD) simulations using the EMS nucleic acid force field produce environment and sequence dependent DNA conformations that closely mimic experimentally derived structures. The parameters were initially developed to reproduce the potential energy surface, as defined by quantum mechanics, for a set of small molecules that can be used as the building blocks for nucleic acid macromolecules (dimethyl phosphate, cyclopentane, tetrahydrofuran, etc.). Then the dihedral parameters were fine tuned using a series of condensed phase MD simulations of DNA and RNA (in zero added salt, 4M NaCl, and 75% ethanol solutions). In the tuning process the free energy surface for each dihedral was derived from the MD ensemble and fitted to the conformational distributions and populations observed in 87 A- and B-DNA x-ray and 17 B-DNA NMR structures. Over 41 nanoseconds of MD simulations are presented which demonstrate that the force field is capable of producing stable trajectories, in the correct environments, of A-DNA, double stranded A-form RNA, B-DNA, Z-DNA, and a netropsin-DNA complex that closely reproduce the experimentally determined and/or canonical DNA conformations. Frequently the MD averaged structure is closer to the experimentally determined structure than to the canonical DNA conformation. MD simulations of A- to B- and B- to A-DNA transitions are also shown. A-DNA simulations in a low salt environment cleanly convert into the B-DNA conformation and converge into the RMS space sampled by a low salt simulation of the same sequence starting from B-DNA. in MD simulations using the EMS force field the B-form of d(GGGCCC), in a 75% ethanol solution converts into the A-form. Using the same methodology, parameters, and conditions the A-form of d(AAATTT)(2) correctly converts into the B-DNA conformation. These studies demonstrate that the force field is capable of reproducing both environment and sequence dependent DNA structures. The 41 nanoseconds (nsec) of MD simulations presented in this paper paint a global picture which suggests that the DNA structures observed in low salt solutions are largely due to the favorable internal energy brought about by the nearly uniform screening of the DNA electrostatics. While the conformations sampled in high salt or mixed solvent environments occur from selective and asymmetric screening of the phosphate groups and DNA grooves, respectively, brought about by sequence induced ion and solvent packing.