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

revised on 06.01.2020, 07:47 and posted on 07.01.2020, 07:19 by Braden Kelly, William Smith
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 drug-like 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.


Natural Sciences and Engineering Research Council of Canada (Strategic Program grant no. STPGP 479466-15)


Email Address of Submitting Author


University of Guelph



ORCID For Submitting Author


Declaration of Conflict of Interest

no conflict of interest

Version Notes

Latest version (3) fixed bug in periodic boundary conditions of neighbor-list search of python script for updating partial charges which slightly changed some numerical results.