QM/MM-Based Fitting of Atomic Polarizabilities for Use in Condensed-Phase Biomolecular Simulation.

Accounting for electronic polarization effects in biomolecular simulation (by using a polarizable force field) can increase the accuracy of simulation results. However, the use of gas-phase estimates of atomic polarizabilities αi usually leads to overpolarization in condensed-phase systems. In the current work, a combined QM/MM approach has been employed to obtain condensed-phase estimates of atomic polarizabilities for water and methanol (QM) solutes in the presence of (MM) solvents of different polarity. In a next step, the validity of the linear response and isotropy assumptions were evaluated based on the observed condensed-phase distributions of αi values. The observed anisotropy and low average values for the polarizability of methanol's carbon atom in polar solvents was explained in terms of strong solute-solvent interactions involving its adjacent hydroxyl group. Our QM/MM estimates for atomic polarizabilities were found to be close to values used in previously reported polarizable water and methanol models. Using our estimate for αO of methanol, a single set of polarizable force field parameters was obtained that is directly transferable between environments of different polarity.