Calculating the sensitivity and robustness of binding free energy calculations to force field parameters

Gabriel Rocklin*, David L. Mobley, Ken A. Dill

*Corresponding author for this work

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Binding free energy calculations offer a thermodynamically rigorous method to compute protein-ligand binding, and they depend on empirical force fields with hundreds of parameters. We examined the sensitivity of computed binding free energies to the ligand's electrostatic and van der Waals parameters. Dielectric screening and cancellation of effects between ligand-protein and ligand-solvent interactions reduce the parameter sensitivity of binding affinity by 65%, compared with interaction strengths computed in the gas-phase. However, multiple changes to parameters combine additively on average, which can lead to large changes in overall affinity from many small changes to parameters. Using these results, we estimate that random, uncorrelated errors in force field nonbonded parameters must be smaller than 0.02 e per charge, 0.06 Å per radius, and 0.01 kcal/mol per well depth in order to obtain 68% (one standard deviation) confidence that a computed affinity for a moderately sized lead compound will fall within 1 kcal/mol of the true affinity, if these are the only sources of error considered.

Original languageEnglish (US)
Pages (from-to)3072-3083
Number of pages12
JournalJournal of Chemical Theory and Computation
Volume9
Issue number7
DOIs
StatePublished - Jul 9 2013

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Computer Science Applications

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