Yingkai ZHANG
New York University

Reliable molecular modeling of complex systems is critically dependent on the accuracy of the employed molecular mechanical force field. The present chapter describes our recent efforts to elucidate origin of one key limitation of current force fields, and thus to facilitate the development of a new generation of ab initio quantum mechanics based force fields. Our theoretical approaches center on a recently developed density-based energy decomposition analysis (DEDA) method [J. Chem. Phys., 131, 164112 (2009)]. This new advance allows an unprecedented clean separation of intermolecular interactions into very meaningful individual terms for force field analysis and development. Here we first employed the DEDA approach to tackle one well-known challenge for widely used biomolecular force fields, which is the description of hydrogen bonding directionality at the receptor atom. Contrary to the conventional wisdom, we find that the sum of electrostatic and van der Waals interaction components is the dominant factor in determining directional dependence of hydrogen bonding, while the density relaxation term, including both polarization and charge-transfer contributions, plays a very minor role. Then using the DEDA results as reference, we demonstrate that the main failure coming from the atomic point charge model can be overcome largely by introducing extra charge sites or higher order multipole moments. Among all the electrostatic models explored, the smeared charge distributed multipole model (up to quadrupole), which also takes account of charge penetration effects, gives the best agreement with the corresponding DEDA results. Finally, we found that a B3LYP-D3 dispersion term, which is screened at short-range and has a correct long-rang behavior, plus a Born-Mayer exponential function for repulsion is an excellent function form to model vdW interactions. In combination with a smeared charge multipole model for electrostatics interactions, the resulted force field is found to yield excellent results in reproducing rare gas interaction energies calculated at the CCSD(T)/CBS level. These progresses have set a solid foundation for systematic force field development based on first principal quantum mechanical calculations.