Self-Guided Molecular Dynamics Simulation for Efficient Conformational Search

Conformational searching is a basic approach in theoretical and computational chemistry, and molecular dynamics [MD] simulation is a powerful computational tool to study structural, thermodynamic, and kinetic properties of molecular systems. In this paper, we report a new MD simulation method with the primary goal of improving dramatically the conformational searching efficiency in an MD simulation in order to study slow events in physics, chemistry, and biology. This new MD simulation method was based upon a new equation of motion in which a guiding force was introduced, in addition to the instantaneous force, to accelerate the systematic motion. This guiding force may be calculated as a time average of the instantaneous force from the trajectory obtained from the very same MD simulation. Bonded substructures were defined for molecular systems in order to enhance effectively both the inter- and intramolecular systematic motions. The improvement of the overall conformational searching efficiency and the possible alterations of ensemble properties and the conformational distribution of the system were investigated through comparative simulations of two peptide systems, an alanine dipeptide and a 16-residue synthetic peptide, both in vacuum and in explicit water. We demonstrated that the self-guided MD simulation method improved conformational searching efficiency but did not significantly alter the ensemble average properties and the conformational distributions of the systems. The successful helix-folding simulations of the 16-residue synthetic peptide both in vacuum and in explicit water clearly showed that the self-guided MD simulations achieved a dramatic enhancement in the conformational searching efficiency and showed an extraordinary ability to overcome energy barriers, as compared to the conventional MD simulations. Our results suggest that this new MD simulation method may be used as a powerful tool to study many important yet slow events or processes in physics, chemistry, and biology.