The incorporation of hydration forces determined by continuum electrostatics into molecular mechanics simulations

Abstract

AbstractA new technique is presented for incorporating hydration forces into molecular mechanics simulations. The method assumes the classical continuum approximation, where a solvated molecule is represented as a low‐dielectric cavity of arbitrary shape embedded in a continuous region of high dielectric constant. Electrostatic effects are computed by first calculating the distribution of polarization charge (induced by the configuration of solute fixed charges) at the molecular surface. The hydration force at a particular atom is then found as the sum of the coulombic interaction with the induced surface charge, plus a purely mechanical contribution that arises from the pressure of the polarized solvent as it is pulled toward the solute. A procedure is developed to use the computed hydration forces in conjunction with the CHARMM molecular mechanics package to carry out energy minimizations in which the effects of solvation are explicitly included. This new technique also allows a detailed analysis of the relative balance of coulombic, hydration, and steric energies as a function of molecular conformation. The method is applied to the test case of a zwitterionic tripeptide (LYS‐GLY‐GLU), and the computational results suggest that hydration effects can play a significant role in determining a stable conformation for a solvated polar molecule. The future application to larger molecules is discussed.