A Combination of the Sequential QM/MM and the Free Energy Gradient Methodologies with Applications

Abstract

To obtain stable states (SS) and transition states (TS) in chemical reactions in condensed phase, the free energy gradient (FEG) method was proposed in 1998 as an optimization method on a multidimensional free energy surface (FES). Analogous to the method for the Born Oppenheimer potential energy surface (PES) using ab initio molecular orbital calculation, the FEG method utilizes the force and Hessian on the FES, which can be adiabatically calculated by molecular dynamics (MD) or Monte Carlo (MC) methods, and, originally, the free energy (FE) perturbation theory. In fact, since then, a number of excellent approximate methods have been developed, e.g., the averaged solvent electrostatic potential (ASEP)/MD method and the average solvent electrostatic configuration (ASEC) method. In this chapter, the FEG methodology is reviewed in general and a future perspective to explore the FE landscape is introduced together with several applications of these methods. Based on computational demands and on the numerical accuracy, we believe that a family of the FEG methodologies should become more efficient as one strategic setting and will play promising and important roles to survey condensed state chemistry on the basis of recent supercomputing technology.