The configurational dependence of binding free energies: A Poisson-Boltzmann study of Neuraminidase inhibitors

CJ Woods, MA King, JW Essex*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

9 Citations (Scopus)

Abstract

The linear finite difference Poisson-Boltzmann (FDPB) equation is applied to the calculation of the electrostatic binding free energies of a group of inhibitors to the Neuraminidase enzyme. An ensemble of enzyme-inhibitor complex conformations was generated using Monte Carlo simulations and the electrostatic binding free energies of subtly different configurations of the enzyme-inhibitor complexes were calculated. It was seen that the binding free energies calculated using FDPB depend strongly on the configuration of the complex taken from the ensemble. This configurational dependence was investigated in detail in the electrostatic hydration free energies of the inhibitors. Differences in hydration energies of up to 7 kcal mol(-1) were obtained for root mean square (RMS) structural deviations of only 0.5 Angstrom. To verify the result, the grid size and parameter dependence of the calculated hydration free energies were systematically investigated. This showed that the absolute hydration free energies calculated using the FDPB equation were very sensitive to the values of key parameters, but that the configurational dependence of the free energies was independent of the parameters chosen. Thus just as molecular mechanics energies are very sensitive to configuration, and single-structure values are not typically used to score binding free energies, single FDPB energies should be treated with the same caution.

Original languageEnglish
Pages (from-to)129-144
Number of pages16
JournalJournal of Computer-Aided Molecular Design
Volume15
Issue number2
Publication statusPublished - Feb 2001

Keywords

  • SOLVENT
  • SOLVATION FREE-ENERGIES
  • ELECTROSTATIC CONTRIBUTIONS
  • snapshot
  • ACCURACY
  • DYNAMICS
  • conformation
  • affinity
  • ensemble
  • EQUATION
  • implicit solvent
  • SIMULATIONS
  • DNA
  • MODELS

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