Molecular dynamics simulations of DNA: force field evaluation and backbone substate dynamics in free and protein-bound DNA

Computer simulations of biomolecules can provide insight into biological structure and dynamics at the atomic level. For simulations to be accurate and reliable, the underlying force #12;eld that describes that system has to tested and assessed against experimental values. Evaluating the latest AMBER nucleic acids force #12;elds at microsecond time scales is important for determining how updated force #12;eld parameter sets compare to earlier models and updated, competing models. The latest two improvements to the AMBER nucleic acid force #12;eld were compared to each other and previous, widely used versions. Both of the latest versions, bsc1 and OL15, showed improvement over earlier versions and reproduced many structural properties in agreement with nuclear magnetic resonance (NMR) and X-ray crystallography experiments. Having a force #12;eld that accurately models duplex DNA is important, but it is also necessary to validate protein-nucleic acid simulations. To examine this, the E2-DNA system was chosen for simulations to see if DNA backbone substates observed in the X-ray structure were reproducible in simulations. In particular, the BI/BII substates were scrutinized. The BI substate is dominant in duplex DNA but #15; and #16; dihedrals populate both trans/gauche- (t/g-) and gauche-/trans (g-/t) conformations, the latter being the BII state. It was determined that dinucleotide steps crystallized in the BII were correspondingly highly-populated in simulations. Additionally, #15; and #16; dihedrals were manipulated to decoy states and found to converge to native distributions on the microsecond time scale in E2-bound DNA, and in less time for free DNA. During the investigation of BII substates in E2-DNA, the surprising observation was made that BI/BII transitions are dominant modes of motion in E2-bound DNA. This inspired research into whether these modes are sequence-dependent or completely induced by the E2 protein, and if the dynamics are conserved across E2 types. Simulations of E2-DNA found that the BII state is determined by a combination of DNA sequence and E2 binding partner.