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

Abstract

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.

A Simple Method for Including Polarization Effects in Solvation Free Energy Calculations When Using Fixed-Charge Force Fields: Alchemically Polarized Charges.

“…The perturbation in the reverse direction will necessarily use the partial charges for state b in both states. The average of these two perturbations has been shown previously 43 to be equivalent to doing two perturbations characterized by both using the same partial charges, which are the average of the two sets.…”

“…28 of the molecules were previously studied using our OTFP method. 43 We added to this test set four 4 All ∆G hyd calculations were performed in the NVT ensemble. We first determined the density for the OPC3 water model by following the protocol used in our previous study 43 for the SPC/E and TIP3P water models.…”

“…43 We added to this test set four 4 All ∆G hyd calculations were performed in the NVT ensemble. We first determined the density for the OPC3 water model by following the protocol used in our previous study 43 for the SPC/E and TIP3P water models. This entailed performing 10 independent N P T simulations at T = 298.15 K and P = 1 bar, for 2000 water molecules.…”

“…10 We recently proposed a method for explicitly incorporating polarization into a fixedcharge FF free energy calculation, called the OTFP (on-the-fly-polarization) method. 43 This approach decouples the electric field generated by the solvent's MM partial charges by scaling the MM partial charges in a QM/MM snapshot proportionally to the Coulombic decoupling parameter λ coul . This allows polarity in the solute partial charges to evolve from being completely unpolarized in vacuum to fully polarized in solution.…”

“…They can be treated either by explicitly polarizable force fields or potentially by our OTFP method. 43 We test our methodology on 45 different solute molecules that range from small polar molecules to large drug-like molecules. We consider Minimal Basis Iterative Stockholder (MBIS) and RESP partial charges.…”