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  Non-equilibrium approach for binding free energies in cyclodextrins in SAMPL7: force fields and software

Khalak, Y., Tresadern, G., de Groot, B. L., & Gapsys, V. (2021). Non-equilibrium approach for binding free energies in cyclodextrins in SAMPL7: force fields and software. Journal of Computer-Aided Molecular Design, 35(1), 49-61. doi:10.1007/s10822-020-00359-1.

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 Creators:
Khalak, Y1, Author              
Tresadern, G., Author
de Groot, B. L.2, Author              
Gapsys, V.3, Author              
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_578573              
2Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society, ou_578631              
3Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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Free keywords: Alchemy; Non-equilibrium free energy calculations; Force field
 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 1.38kcal/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.

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Language(s): eng - English
 Dates: 2020-11-242021-01
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1007/s10822-020-00359-1
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Title: Journal of Computer-Aided Molecular Design
Source Genre: Journal
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Pages: - Volume / Issue: 35 (1) Sequence Number: - Start / End Page: 49 - 61 Identifier: -