Refinement of homology-based protein structures by molecular dynamics simulation techniques

The use of classical molecular dynamics simulations, performed in explicit water, for the refinement of structural models of proteins generated ab initio or based on homology has been investigated. The study involved a test set of 15 proteins that were previously used by Baker and coworkers to assess the efficiency of the ROSETTA method for ab initio protein structure prediction. For each protein, four models generated using the ROSETTA procedure were simulated for periods of between 5 and 400 nsec in explicit solvent, under identical conditions. In addition, the experimentally determined structure and the experimentally derived structure in which the side chains of all residues had been deleted and then regenerated using the WHATIF program were simulated and used as controls. A significant improvement in the deviation of the model structures from the experimentally determined structures was observed in several cases. In addition, it was found that in certain cases in which the experimental structure deviated rapidly from the initial structure in the simulations, indicating internal strain, the structures were more stable after regenerating the side-chain positions. Overall, the results indicate that molecular dynamics simulations on a tens to hundreds of nanoseconds time scale are useful for the refinement of homology or ab initio models of small to medium-size proteins.