Binding free energies for the SAMPL8 CB8 Drugs of Abuse challenge from umbrella sampling combined with Hamiltonian replica exchange

Umbrella sampling along a one-dimensional order parameter in combination with Hamiltonian replica exchange was employed to calculate the binding free energy of five guest molecules with known affinity to cucurbit[8]uril. A simple empirical approach correcting for the overestimation of the affinity by the GAFF force field was proposed and subsequently applied to the seven guest molecules of the Drugs of Abuse SAMPL8 challenge. Compared to the uncorrected binding free energies, the systematic error decreased but quantitative agreement with experiment was only reached for a few compounds. From a retrospective analysis a weak point of the correction term was identified.

Automated summary

This study employed umbrella sampling along a one-dimensional order parameter combined with Hamiltonian replica exchange to calculate the binding free energy of five guest molecules known to have affinity for cucurbit[8]uril. An empirical approach was proposed to correct for the overestimation of affinity by the GAFF force field, and subsequently applied to seven guest molecules in the Drugs of Abuse SAMPL8 challenge. While the systematic error decreased, quantitative agreement with experiment was only reached for a few compounds.