Prediction of cyclohexane-water distribution coefficients for the SAMPL5 data set using molecular dynamics simulations with the OPLS-AA force field

Ian M. Kenney, Oliver Beckstein, Bogdan I. Iorga

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

All-atom molecular dynamics simulations were used to predict water-cyclohexane distribution coefficients (Formula presented.) of a range of small molecules as part of the SAMPL5 blind prediction challenge. Molecules were parameterized with the transferable all-atom OPLS-AA force field, which required the derivation of new parameters for sulfamides and heterocycles and validation of cyclohexane parameters as a solvent. The distribution coefficient was calculated from the solvation free energies of the compound in water and cyclohexane. Absolute solvation free energies were computed by an established protocol using windowed alchemical free energy perturbation with thermodynamic integration. This protocol resulted in an overall root mean square error in (Formula presented.) of almost 4 log units and an overall signed error of −3 compared to experimental data. There was no substantial overall difference in accuracy between simulating in NVT and NPT ensembles. The signed error suggests a systematic error but the experimental (Formula presented.) data on their own are insufficient to uncover the source of this error. Preliminary work suggests that the major source of error lies in the hydration free energy calculations.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalJournal of Computer-Aided Molecular Design
DOIs
StateAccepted/In press - Aug 31 2016

Fingerprint

Molecular Dynamics Simulation
Cyclohexane
cyclohexane
field theory (physics)
Free energy
Molecular dynamics
free energy
molecular dynamics
Water
Solvation
Computer simulation
Research Design
coefficients
predictions
water
solvation
simulation
Thermodynamics
Atoms
Molecules

Keywords

  • Cyclohexane-water distribution coefficients
  • Free energy perturbation
  • Ligand parameterization
  • Molecular dynamics
  • OPLS-AA force field
  • Solvation free energy
  • Thermodynamic integration

ASJC Scopus subject areas

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

Cite this

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title = "Prediction of cyclohexane-water distribution coefficients for the SAMPL5 data set using molecular dynamics simulations with the OPLS-AA force field",
abstract = "All-atom molecular dynamics simulations were used to predict water-cyclohexane distribution coefficients (Formula presented.) of a range of small molecules as part of the SAMPL5 blind prediction challenge. Molecules were parameterized with the transferable all-atom OPLS-AA force field, which required the derivation of new parameters for sulfamides and heterocycles and validation of cyclohexane parameters as a solvent. The distribution coefficient was calculated from the solvation free energies of the compound in water and cyclohexane. Absolute solvation free energies were computed by an established protocol using windowed alchemical free energy perturbation with thermodynamic integration. This protocol resulted in an overall root mean square error in (Formula presented.) of almost 4 log units and an overall signed error of −3 compared to experimental data. There was no substantial overall difference in accuracy between simulating in NVT and NPT ensembles. The signed error suggests a systematic error but the experimental (Formula presented.) data on their own are insufficient to uncover the source of this error. Preliminary work suggests that the major source of error lies in the hydration free energy calculations.",
keywords = "Cyclohexane-water distribution coefficients, Free energy perturbation, Ligand parameterization, Molecular dynamics, OPLS-AA force field, Solvation free energy, Thermodynamic integration",
author = "Kenney, {Ian M.} and Oliver Beckstein and Iorga, {Bogdan I.}",
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AU - Kenney, Ian M.

AU - Beckstein, Oliver

AU - Iorga, Bogdan I.

PY - 2016/8/31

Y1 - 2016/8/31

N2 - All-atom molecular dynamics simulations were used to predict water-cyclohexane distribution coefficients (Formula presented.) of a range of small molecules as part of the SAMPL5 blind prediction challenge. Molecules were parameterized with the transferable all-atom OPLS-AA force field, which required the derivation of new parameters for sulfamides and heterocycles and validation of cyclohexane parameters as a solvent. The distribution coefficient was calculated from the solvation free energies of the compound in water and cyclohexane. Absolute solvation free energies were computed by an established protocol using windowed alchemical free energy perturbation with thermodynamic integration. This protocol resulted in an overall root mean square error in (Formula presented.) of almost 4 log units and an overall signed error of −3 compared to experimental data. There was no substantial overall difference in accuracy between simulating in NVT and NPT ensembles. The signed error suggests a systematic error but the experimental (Formula presented.) data on their own are insufficient to uncover the source of this error. Preliminary work suggests that the major source of error lies in the hydration free energy calculations.

AB - All-atom molecular dynamics simulations were used to predict water-cyclohexane distribution coefficients (Formula presented.) of a range of small molecules as part of the SAMPL5 blind prediction challenge. Molecules were parameterized with the transferable all-atom OPLS-AA force field, which required the derivation of new parameters for sulfamides and heterocycles and validation of cyclohexane parameters as a solvent. The distribution coefficient was calculated from the solvation free energies of the compound in water and cyclohexane. Absolute solvation free energies were computed by an established protocol using windowed alchemical free energy perturbation with thermodynamic integration. This protocol resulted in an overall root mean square error in (Formula presented.) of almost 4 log units and an overall signed error of −3 compared to experimental data. There was no substantial overall difference in accuracy between simulating in NVT and NPT ensembles. The signed error suggests a systematic error but the experimental (Formula presented.) data on their own are insufficient to uncover the source of this error. Preliminary work suggests that the major source of error lies in the hydration free energy calculations.

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KW - Thermodynamic integration

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