Project: Research council

Project Details


Simulation of potential-energy and free-energy profiles for reaction steps in putative mechanisms for sialidases using hybrid quantum/classical methods.

Layman's description

Mapping the complex network of possible chemical reaction pathways that could be used by an enzyme implicated in influenza in order to point towards design of a better anti-flu drug.

Key findings

We demonstrated that the mechanism of action of several different sialidases is essentially common and involves both the covalent intermediate (as with other retaining glycosidases) and the oxacarbenium. Both species are accessible within the enzyme active site under normal physiological conditions, but probably the rate-determining transition state is that for general base-catalysed nucleophilic substitution leading to the covalent intermediate. Since the two species differ significantly in their charge distribution, this result may have an important bearing upon the design of new and better inhibitors as transition-state analogues; whereas Relenza and Tamiflu both used DANA as their template, it might be fruitful to design mimics for the transition state of the actual rate-determining step.
Effective start/end date1/04/0531/03/08


  • Biotechnology and Biological Sciences Research Council

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  • Research Output

    Does glycosyl transfer involve an oxacarbenium intermediate? Computational simulation of the lifetime of the methoxymethyl cation in water

    Williams, I. H., Ruiz-Pernia, J. J. & Tunon, I., 2011, In : Pure and Applied Chemistry. 83, 8, p. 1507-1514 8 p.

    Research output: Contribution to journalArticle

  • 8 Citations (Scopus)
    123 Downloads (Pure)

    Computational mutagenesis reveals the role of active-site tyrosine in stabilising a boat conformation for the substrate: QM/MM molecular dynamics studies of wild-type and mutant xylanases

    Soliman, M. E. S., Ruggiero, G. D., Pernia, J. J. R., Greig, I. R. & Williams, I. H., 7 Feb 2009, In : Organic and Biomolecular Chemistry. 7, 3, p. 460-468 9 p.

    Research output: Contribution to journalArticle

    Open Access
  • 31 Citations (Scopus)
    133 Downloads (Pure)

    Mechanism of glycoside hydrolysis: A comparative QM/MM molecular dynamics analysis for wild type and Y69F mutant retaining xylanases

    Soliman, M., Ruiz-Pernía, J. J., Greig, I. & Williams, I., 2009, In : Organic and Biomolecular Chemistry. 7, 24, p. 5236-5244 9 p.

    Research output: Contribution to journalArticle

    Open Access
  • 24 Citations (Scopus)
    208 Downloads (Pure)