Prediction of hydration free energies for the SAMPL4 diverse set of compounds using molecular dynamics simulations with the OPLS-AA force field

Oliver Beckstein, Anaïs Fourrier, Bogdan I. Iorga

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

All-atom molecular dynamics computer simulations were used to blindly predict the hydration free energies of a range of small molecules as part of the SAMPL4 challenge. Compounds were parametrized on the basis of the OPLS-AA force field using three different protocols for deriving partial charges: (1) using existing OPLS-AA atom types and charges with minor adjustments of partial charges on equivalent connecting atoms and derivation of new parameters for a number of distinct chemical groups (N-alkyl imidazole, nitrate) that were not present in the published force field; (2) calculation of quantum mechanical charges via geometry optimization, followed by electrostatic potential (ESP) fitting, using Jaguar at the LMP2/cc-pVTZ(-F) level; and (3) via geometry optimization and CHelpG charges (Gaussian09 at the HF/6-31G*level), followed by two-stage RESP fitting. The absolute hydration free energy was computed by an established protocol including alchemical free energy perturbation with thermodynamic integration. The use of standard OPLS-AA charges (protocol 1) with a number of newly parametrized charges and the use of histidine derived parameters for imidazole yielded an overall root mean square deviation of the prediction from the experimental data of 1.75 kcal/mol. The precision of our results appears to be mainly limited by relatively poor reproducibility of the Lennard-Jones contribution towards the solvation free energy, for which we observed large variability that could be traced to a strong dependence on the initial system conditions.

Original languageEnglish (US)
Pages (from-to)265-276
Number of pages12
JournalJournal of Computer-Aided Molecular Design
Volume28
Issue number3
DOIs
StatePublished - Mar 2014

Keywords

  • Free energy perturbation
  • Hydration free energy
  • Ligand parametrization
  • Molecular dynamics
  • OPLS-AA force field
  • Thermodynamic integration

ASJC Scopus subject areas

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

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