Can Brownian Dynamics be a Useful Tool for Structure-Based Drug Design?

Molecular simulations play important roles in computer-aided drug design (CADD). Especially, these calculations are useful for the analyses of 3D structures of biopolymers, such as proteins, nucleic acids or sugar chains, in structure-based drug design (SBDD) trials. The molecular dynamics (MD) simulation is most widely used for the molecular simulations of biopolymers, and it plays significant roles not only in CADD but also fundamental biological researches. On the other hand, because calculations of solvent effects caused by water molecules surrounding biopolymers are indispensable to MD simulations of biopolymers, high computational costs are often required for MD. Brownian dynamics (BD) simulation is one of the molecular simulation methods. In BD simulations, solvent effects are represented by random power and viscosity of the solvent without using explicit water molecules. Because of the implicit solvent model, BD calculations require much less computational resources than MD with explicit solvent molecules. Recently, we developed BD program, named as “brownian”. The operationality of this program is very similar to AMBER, which is one of the most widely used MD program especially for biopolymers. For example, parameter variables which have same names between brownian and AMBER have same meanings in both programs. The command options and input file formats of these two programs are also similar to each other. The similarity of operationality is advantage of brownian, because BD simulations can be easily carried out even if users are not skillful for BD. In addition, because brownian can read AMBER topology and coordinate files without any additive operation, it can use all types of AMBER force fields, which is one of the most reliable force field for biological systems. Although we have already tested the brownian for simulating induced fit caused by protein-ligand docking, more detailed tests are required for investigating whether brownian can be used for CADD or not. In this study, the structural stabilities of the wild type and mutant proteins were calculated, and the ability of brownian for biopolymer simulations were evaluated by comparing these results.