10.26434/chemrxiv.10031789.v3
Braden Kelly
William Smith
Alchemical Hydration Free Energy Calculations Using Molecular Dynamics with Explicit Polarization and Induced Polarity Decoupling: An On-the-Fly Approach
2020
ChemRxiv
Chemical potential
Hydration Free Energy Calculations
Partial Charge Models
Free Energy Calculations
2020-01-07 07:19:13
article
https://chemrxiv.org/articles/preprint/Alchemical_Hydration_Free_Energy_Calculations_Using_Molecular_Dynamics_with_Explicit_Polarization_and_Induced_Polarity_Decoupling_An_OTFP_Approach/10031789
<div>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.</div>