Stability tests on known and misfolded structures with discrete and all atom molecular dynamics simulations

Abstract

The brevity of molecular dynamics simulations often limits their utility in developing and evaluating structural models of proteins. The duration of simulations can be increased greatly using discrete molecular dynamics (DMD). However, the trade off is that coarse graining, implicit solvent, and other time-saving procedures reduce the accuracy of DMD simulations. Here we address some of these issues by comparing results of DMD and conventional all atom MD simulations on proteins of known structure and misfolded proteins. DMD simulations were performed at a range of temperatures to identify a ‘physiological’ temperature for DMD that mimicked molecular motions of conventional MD simulations at 310 K. We also compared results obtained with a new implicit solvent model developed here based on Miyazawa–Jernigan interaction pair potential to those obtained with a previously used model based on Kyte–Doolittle hydropathy scale. We compared DMD and all atom molecular dynamics with explicit water by simulating both correctly and incorrectly folded structures, and monomeric and dimeric α β-barrel structures to analyze the ability of these procedures to distinguish between good and bad models. Deviations from the correct structures were substantially greater with DMD, as would be expected from coarse-graining and longer simulation time. Deviations were smallest for β-strands and greatest for coiled loops. Structures of the incorrectly folded models were very poorly preserved during the DMD simulations; but both methods were able to distinguish between the correct and the incorrect structures based on differences in the magnitudes of the root mean squared deviation (RMSD) from the starting conformation.