Combining crystallographic information and an aspherical-atom data bank in the evaluation of the electrostatic interaction energy in an enzyme–substrate complex: influenza neuraminidase inhibition
- Department of Chemistry, State University of New York at Buffalo, NY 14260 (United States)
- Department of Chemistry, University of Warsaw, ul. Pasteura 1, 02-093 Warszawa (Poland)
The electrostatic component of the enzyme/inhibitor interaction of a wide range influenza neuraminidases and inhibitors has been analyzed using transferable aspherical-atom densities from a recently compiled databank. Results are subdivided into the contributions of individual active-site residues and different functional groups of the inhibitors, and the effect of the Arg292→Lys mutation is considered. Although electrostatic interactions contribute only a part of the interaction energies between macromolecules, unlike dispersion forces they are highly directional and therefore dominate the nature of molecular packing in crystals and in biological complexes and contribute significantly to differences in inhibition strength among related enzyme inhibitors. In the reported study, a wide range of complexes of influenza neuraminidases with inhibitor molecules (sialic acid derivatives and others) have been analyzed using charge densities from a transferable aspherical-atom data bank. The strongest interactions of the residues are with the acidic group at the C2 position of the inhibitor (∼−300 kJ mol{sup −1} for —COO{sup −} in non-aromatic inhibitors, ∼−120–210 kJ mol{sup −1} for —COO{sup −} in aromatic inhibitors and ∼−450 kJ mol{sup −1} for —PO{sub 3}{sup 2−}) and with the amino and guanidine groups at C4 (∼−250 kJ mol{sup −1}). Other groups contribute less than ∼100 kJ mol{sup −1}. Residues Glu119, Asp151, Glu227, Glu276 and Arg371 show the largest variation in electrostatic energies of interaction with different groups of inhibitors, which points to their important role in the inhibitor recognition. The Arg292→Lys mutation reduces the electrostatic interactions of the enzyme with the acidic group at C2 for all inhibitors that have been studied (SIA, DAN, 4AM, ZMR, G20, G28, G39 and BCZ), but enhances the interactions with the glycerol group at C6 for inhibitors that contain it. This is in agreement with the lower level of resistance of the mutated virus to glycerol-containing inhibitors compared with the more hydrophobic derivatives.
- OSTI ID:
- 22351177
- Journal Information:
- Acta Crystallographica. Section D: Biological Crystallography, Vol. 65, Issue Pt 5; Other Information: PMCID: PMC2672818; PMID: 19390154; PUBLISHER-ID: dz5152; OAI: oai:pubmedcentral.nih.gov:2672818; Copyright (c) International Union of Crystallography 2009; Country of input: International Atomic Energy Agency (IAEA); ISSN 0907-4449
- Country of Publication:
- Denmark
- Language:
- English
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