Alchemical Hydration Free-Energy Calculations Using Molecular Dynamics with Explicit Polarization and Induced Polarity Decoupling: An On–the–Fly Polarization Approach

We
present a methodology using fixed charge force fields for alchemical
solvation free energy calculations which accounts for the change in
polarity that the solute experiences as it transfers from the gas-phase
to the condensed phase. We update partial charges using QM/MM snapshots,
decoupling the electric field appropriately when updating the partial
charges. We also show how to account for the cost of self-polarization.
We test our methodology on 30 molecules ranging from small polar to
large druglike molecules. We use Minimum Basis Iterative Stockholder
(MBIS), Restrained Electrostatic Potential (RESP), and AM1-BCC partial
charge methodologies. Using our method with MP2/cc-pVTZ and MBIS partial
charges yields an average absolute deviation (AAD) of 6.3 kJ·mol–1 in comparison with the AM1-BCC result of 8.6 kJ·mol–1. AM1-BCC is within experimental uncertainty on 10%
of the data compared to 30% with our method. We conjecture that results
can be further improved by using Lennard-Jones and torsional parameters
refitted to MBIS and RESP partial charge methods that use high levels
of theory.