Variational Implicit Solvation with Application to Identifying Ligand-Protein Binding Sites

Jianwei Che/Bo Li
GNF/Math, UCSD


ABSTRACT

The variational implicit-solvent model (VISM) is an advanced solvation theory and computational approach. It is based on the minimization of a solvation free-energy functional of all possible solute-solvent interfaces, i.e., dielectric boundaries. The free energy includes the volume contribution, interfacial energy with a curvature-corrected surface tension, solute-solvent van der Waals interaction energy, and electrostatic energy. For years, we have developed a robust level-set method to numerically minimize such a functional for arbitrarily shaped biological molecules. Our intensive computational results have demonstrated that this efficient approach can capture the wet and dry states of hydration, and subtle charge effects; and can provide quantitatively good estimates of solvation free energies. In this talk, we review what we have achieved with the level-set VISM, describe some initial work on modeling the solvent dynamics with the VISM dielectric boundary force, and report our recent level-set VISM application to identifying ligand-protein binding pockets that are crucial in rational drug design. VISM was initiated in McCammon's group. What is reported here is joint work involving mainly McCammon's group, Joachim Dzubiella, Bo Li, Li-Tien Cheng, Jianwei Che, Zhongming Wang, Shenggao Zhou, Zhuojun Guo, Michael White, Hui Sun, and Yanxiang Zhao. Our work has been supported by NIH, NSF, and CTBP.