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Precise force-field-based calculations of octanol-water partition coefficients for the SAMPL7 molecules

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Abstract

We predicted water-octanol partition coefficients for the molecules in the SAMPL7 challenge with explicit solvent classical molecular dynamics (MD) simulations. Water hydration free energies and octanol solvation free energies were calculated with a windowed alchemical free energy approach. Three commonly used force fields (AMBER GAFF, CHARMM CGenFF, OPLS-AA) were tested. Special emphasis was placed on converging all simulations, using a criterion developed for the SAMPL6 challenge. In aggregate, over 1000 \(\mu\)s of simulations were performed, with some free energy windows remaining not fully converged even after 1 \(\mu\)s of simulation time. Nevertheless, the amount of sampling produced \(\log P_{ow}\) estimates with a precision of 0.1 log units or better for converged simulations. Despite being probably as fully sampled as can expected and is feasible, the agreement with experiment remained modest for all force fields, with no force field performing better than 1.6 in root mean squared error. Overall, our results indicate that a large amount of sampling is necessary to produce precise \(\log P_{ow}\) predictions for the SAMPL7 compounds and that high precision does not necessarily lead to high accuracy. Thus, fundamental problems remain to be solved for physics-based \(\log P_{ow}\) predictions.

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Acknowledgements

We thank an anonymous referee for pointing out potential problems with gas phase sampling in our simulations. We appreciate the National Institutes of Health for its support of the SAMPL project via R01GM124270 to David L. Mobley (UC Irvine).

Funding

Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Awards Number R01GM118772 and R01GM125081, by GENCI–IDRIS (Grant 2020-A0080711524), by the French National Research Agency (ANR) through grants ANR-10-LABX-33 (LabEx LERMIT) and ANR-14-JAMR-0002-03 (JPIAMR), and by the Région Ile-de-France (grant DIM MAL-INF). Computing time on the Agave cluster of Research Computing at Arizona State University is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Physics, Arizona State University, P.O. Box 871504, Tempe, AZ, 85287-1504, USA

    Shujie Fan

  2. Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, Labex LERMIT, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette, France

    Hristo Nedev & Bogdan I. Iorga

  3. Department of Biology, College of Science, United Arab Emirates University, PO Box 15551, Al Ain, UAE

    Ranjit Vijayan

  4. Department of Physics and Center for Biological Physics, Arizona State University, P.O. Box 871504, Tempe, AZ, 85287-1504, USA

    Oliver Beckstein

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  1. Shujie Fan
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Correspondence to Bogdan I. Iorga or Oliver Beckstein.

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Fan, S., Nedev, H., Vijayan, R. et al. Precise force-field-based calculations of octanol-water partition coefficients for the SAMPL7 molecules. J Comput Aided Mol Des 35, 853–870 (2021). https://doi.org/10.1007/s10822-021-00407-4

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