A Coarse-Grained Simulation Approach for Protein Molecular Conformation Dynamics.

Coarse-grained molecular dynamics simulation is widely accepted for assessment of a large complex biological system, but it may also lead to a misleading conclusion. The challenge is to simulate protein structural dynamics (such as folding-unfolding behavior) due to the lack of a necessary backbone flexibility. This study developed a standard coarse-grained model directly from the protein atomic structure and amino acid coarse-grained FF (such as MARTINI FF v2.2). The atomic structure is used as a parent template to set up the coarse model, which naturally gives a better representation of the initial conditions. We have formulated a computational algorithm to set up protein coarse-grained coordinates and force field topology (such as bonds, angles, and dihedrals). The model was validated by a systematic all atom and coarse-grained simulation of a system containing protein human serum albumin and the drug paclitaxel in a water bath. The bonded force constants were optimized locally by neighboring residue-free energy data and globally by history matching against all atom simulation. The coarse-grained model was then applied for several other proteins and justified its general reliability for modeling protein conformations dynamics. We arrived at such a conclusion with great satisfaction because it describes the initial conditions accurately, applies only standard bonded force constants, and provides a significant backbone flexibility.