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.

ABSTRACT: 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 ( approximately -300 kJ mol(-1) for -COO(-) in non-aromatic inhibitors, approximately -120-210 kJ mol(-1) for -COO(-) in aromatic inhibitors and approximately -450 kJ mol(-1) for -PO(3)(2-)) and with the amino and guanidine groups at C4 ( approximately -250 kJ mol(-1)). Other groups contribute less than approximately 100 kJ mol(-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.

SUBMITTER: Dominiak PM 

PROVIDER: S-EPMC2672818 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature