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

Shujie Fan, Hristo Nedev, Ranjit Vijayan, Bogdan I. Iorga, Oliver Beckstein

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 μs of simulations were performed, with some free energy windows remaining not fully converged even after 1 μs of simulation time. Nevertheless, the amount of sampling produced log Pow 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 Pow 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 Pow predictions.

Original languageEnglish (US)
Pages (from-to)853-870
Number of pages18
JournalJournal of Computer-Aided Molecular Design
Volume35
Issue number7
DOIs
StatePublished - Jul 2021
Externally publishedYes

Keywords

  • Free energy perturbation
  • Molecular dynamics
  • Octanol-water partition coefficient
  • SAMPL7
  • Solvation free energy

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

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