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

The configurational dependence of binding free energies: a Poisson-Boltzmann study of Neuraminidase inhibitors
The configurational dependence of binding free energies: a Poisson-Boltzmann study of Neuraminidase inhibitors
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.
affinity, conformation, ensemble, implicit solvent, snapshot solvation free-energies, electrostatic contributions, dynamics, accuracy, simulations, equation, solvent, models, dna
0920-654X
129-144
Woods, Christopher J.
54c21a03-755f-4977-aa2c-72c1b073e734
King, Michael A.
60520a12-4a45-435b-98bb-420eff76ab34
Essex, Johnathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Woods, Christopher J.
54c21a03-755f-4977-aa2c-72c1b073e734
King, Michael A.
60520a12-4a45-435b-98bb-420eff76ab34
Essex, Johnathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5

Woods, Christopher J., King, Michael A. and Essex, Johnathan W. (2001) The configurational dependence of binding free energies: a Poisson-Boltzmann study of Neuraminidase inhibitors. Journal of Computer-Aided Molecular Design, 15 (2), 129-144. (doi:10.1023/A:1008197913568).

Record type: Article

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.

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More information

Published date: 1 February 2001
Keywords: affinity, conformation, ensemble, implicit solvent, snapshot solvation free-energies, electrostatic contributions, dynamics, accuracy, simulations, equation, solvent, models, dna

Identifiers

Local EPrints ID: 19637
URI: http://eprints.soton.ac.uk/id/eprint/19637
ISSN: 0920-654X
PURE UUID: 12dda6de-6414-4127-a17e-37b62eda6163
ORCID for Johnathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

Catalogue record

Date deposited: 13 Feb 2006
Last modified: 12 Nov 2019 02:01

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