Non-equilibrium approach for binding free energies in cyclodextrins in SAMPL7: force fields and software
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Non‑equilibrium approach for binding free energies in cyclodextrins in SAMPL7: force fields and software Yuriy Khalak1 · Gary Tresadern2 · Bert L. de Groot1 · Vytautas Gapsys1 Received: 30 June 2020 / Accepted: 7 November 2020 © The Author(s) 2020
Abstract In the current work we report on our participation in the SAMPL7 challenge calculating absolute free energies of the host– guest systems, where 2 guest molecules were probed against 9 hosts-cyclodextrin and its derivatives. Our submission was based on the non-equilibrium free energy calculation protocol utilizing an averaged consensus result from two force fields (GAFF and CGenFF). The submitted prediction achieved accuracy of 1.38 kcal∕mol in terms of the unsigned error averaged over the whole dataset. Subsequently, we further report on the underlying reasons for discrepancies between our calculations and another submission to the SAMPL7 challenge which employed a similar methodology, but disparate ligand and water force fields. As a result we have uncovered a number of issues in the dihedral parameter definition of the GAFF 2 force field. In addition, we identified particular cases in the molecular topologies where different software packages had a different interpretation of the same force field. This latter observation might be of particular relevance for systematic comparisons of molecular simulation software packages. The aforementioned factors have an influence on the final free energy estimates and need to be considered when performing alchemical calculations. Keywords Alchemy · Non-equilibrium free energy calculations · Force field
Introduction The computational chemistry community benefits greatly from the periodically organized blinded challenges providing an unbiased evaluation of the state-of-the art techniques available in the field. Over the years the SAMPL challenge has provided opportunities for scientists to predict ligand solvation free energies, octanol-water partition coefficients, protein-ligand and host–guest binding free energies [1–6].
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10822-020-00359-1) contains supplementary material, which is available to authorized users. * Vytautas Gapsys [email protected] 1
Computational Biomolecular Dynamics Group, Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany
Computational Chemistry, Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, 2340 Beerse, Belgium
2
The previous SAMPL challenge (SAMPL6) [5] contained an additional SAMPLing sub-challenge [7], where we took part by probing the sampling efficiency of the non-equilibrium alchemical free energy calculation approach for the absolute binding free energies of host–guest systems. Previously, we have also shown the potential of the non-equilibrium alchemical method in a post-submission evaluation of a dataset from the D3R Grand Challenge 4 by calculating relative binding free
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