Quantum Mechanical Approaches to Biomolecular Simulations: From a Single Electron to Fully Solvated Proteins

Jiali Gao
University of Minnesota, Twin Cities

Atomistic simulation and modeling of biomolecular systems and quantitative analysis of protein-ligand interactions are generally performed with the use of molecular mechanical potentials, or force fields. Although the current force fields have been very successful thanks to the parameterization by many groups around the world in the past half a century, the formalisms and the functional terms have hardly changed. To increase the accuracy and predictability in biomolecular simulation, and ultimately in drug discovery, we have developed a novel theoretical framework for a fully quantal force field, in which the functional form is based on electronic structural theory explicitly. In this paper, I will present a multistate density functional theory (MSDFT) for studying chemical reactions, including proton coupled electron transfer (PCET) processes. Then, for systems that do not involve bond-making and bond-breaking processes, I will present the explicit polarization (X-Pol) theory, which relies on block-localization of molecular fragments, by separating a large molecular system such as a fully solvated protein into subsystem molecular or group fragments. In X-Pol, the total molecular wave function is approximated as a Hartree product of the antisymmetric wave functions of individual fragments. The exchange repulsion, dispersion and charge transfer effects are approximated empirically, or can be determined ab initio. Some recent development and applications are illustrated including a fully solvated protein using a quantal force field.

Back to Workshop I: Design of Drugs and Chemicals that Influence Biology