A new Hybrid Monte Carlo algorithm for protein potential function test and structure refinement

A new Hybrid Monte Carlo (HMC) algorithm has been developed to test protein potential functions and, ultimately, refine protein structures. The main principle of this algorithm is, in each cycle, a new trial conformation is generated by carrying out a short period of molecular dynamics (MD) iterations with a set of random parameters (including the MD time step, the number of MD steps, the MD temperature, and the seed for initial MD velocity assignment); then to accept or reject the new conformation on the basis of the Metropolis criterion. The novelty in this paper is that the potential in MD iterations is different from that in the MC step. In the former, it is a molecular mechanics potential, in the latter it is a knowledge-based potential (KBP). Directed by the KBP, the MD iteration is used to search conformational space for realistic conformations with low KBP energy. It circumvents the difficulty in using KBP functions directly in MD simulation, as KBP functions are typically incomplete, and do not always have continuous derivatives required for the calculation of the forces. The new algorithm has been tested in explorations of conformational space. In these test calculations the KBP energy was found to drop below the value for the native conformation, and the correlation between the root mean square deviation (RMSD) and the KBP energy was shown to be different from the test results in other references. At the present time, the algorithm is useful for testing new KBP functions. Furthermore, if a KBP function can be found for which the native conformation has the lowest energy and the energy/RMSD correlation is good, then this new algorithm also will be a tool for refinement of the theory-based structural models.