Binding free energies for the SAMPL8 CB8 \u201cDrugs of Abuse\u201d challenge from umbrella sampling combined with Hamiltonian replica exchange

Daniel Markthaler,Niels Hansen,Hamzeh Kraus

doi:10.1007/s10822-021-00439-w

Daniel Markthaler, Niels Hansen + Show 1 more

Open Access

https://doi.org/10.1007/s10822-021-00439-w

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Abstract

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.

Highlights

Computational approachAmong the many possible methodological variants to compute binding free energies for host-guest systems within a rigorous thermodynamic framework [1], umbrella sampling (US) [2] has emerged as an easy-to-use approach that is supported by many publicly available pre- and post-analysis tools [3]
We hope that the comparison to other free-energy methods applied to the same host-guest systems within the SAMPL challenge is of use for the continuous evaluation of methods and force fields pushing forward the field of binding free energy calculations, which, for complex systems, often faces a combination of force-field and sampling issues [5, 6]
The binding free energies of guests GT1 to GT5 to CB8 was calculated and used to parametrize an empirical correction model that was applied to the SAMPL8 set of guest molecules

Summary

Introduction

Computational approachAmong the many possible methodological variants to compute binding free energies for host-guest systems within a rigorous thermodynamic framework [1], umbrella sampling (US) [2] has emerged as an easy-to-use approach that is supported by many publicly available pre- and post-analysis tools [3]. For all guest molecules both the protonated and deprotonated form were considered in the binding free energy calculations.

Results

Conclusion