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Protein Science (2004), 13:946-957. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Molecular dynamics and free energy analysis of neuraminidase–ligand interactions

Pascal Bonnet and Richard A. Bryce

School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK

(RECEIVED April 30, 2003; FINAL REVISION October 15, 2003; ACCEPTED January 10, 2004)



Abstract

We report molecular dynamics calculations of neuraminidase in complex with an inhibitor, 4-amino-2-deoxy-2,3-didehydro-N-acetylneuraminic acid (N-DANA), with subsequent free energy analysis of binding by using a combined molecular mechanics/continuum solvent model approach. A dynamical model of the complex containing an ionized Glu119 amino acid residue is found to be consistent with experimental data. Computational analysis indicates a major van der Waals component to the inhibitor-neuraminidase binding free energy. Based on the N-DANA/neuraminidase molecular dynamics trajectory, a perturbation methodology was used to predict the binding affinity of related neuraminidase inhibitors by using a force field/Poisson-Boltzmann potential. This approach, incorporating conformational search/local minimization schemes with distance-dependent dielectric or generalized Born solvent models, correctly identifies the most potent neuraminidase inhibitor. Mutation of the key ligand four-substituent to a hydrogen atom indicates no favorable binding free energy contribution of a hydroxyl group; conversely, cationic substituents form favorable electrostatic interactions with neuraminidase. Prospects for further development of the method as an analysis and rational design tool are discussed.

Keywords: inhibitors of influenza neuraminidase; molecular dynamics; computational analysis of binding free energy; continuum solvent models; perturbation methodology

Abbreviations: DANA, 2-deoxy-2,3-didehydro-N-acetylneuraminic acid • N-DANA, 4-amino-2-deoxy-2,3-didehydro-N-acetylneuraminic acid • GANA, 4-guanidino-2-deoxy-2,3-didehydro-N-acetylneuraminic acid • NMe3-DANA, 4-trimethylamino-2-deoxy-2,3-didehydro-N-acetylneuraminic acid • MD, molecular dynamics • PB, Poisson-Boltzmann • GB, generalized Born

Reprint requests to: Richard A. Bryce, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK; e-mail: R.A.Bryce{at}man.ac.uk; fax: 44-161-275-2481.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03129704


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