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

Ian H Williams, J Javier Ruiz-Pernia, Inaki Tunon

Research output: Contribution to journalArticle

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Abstract

2D free-energy surfaces for transfer of the methoxymethyl cation between two water molecules are constructed from molecular dynamics (MD) simulations in which these atoms are treated quantum-mechanically within a box of 1030 classical solvent water molecules at 300 K. This provides a simple model for glycosyl transfer in water. The AM1/TIP3P surfaces with 2D-spline corrections at either MPWB1K/6-31+G(d,p) or MP2/6-31+G(d,p) contain a shallow free-energy well corresponding to an oxacarbenium ion intermediate in a DN*AN mechanism. MD analysis at three temperatures leads to a classical estimate of the lifetime of the methoxymethyl cation in water; when quantum corrections for vibrational zero-point energy are included, the lifetime is estimated to be about 1 ps, in agreement with the best experimental estimate. This suggests that computational simulation, with appropriate high-level correction, is a reliable tool to obtain detailed and reliable mechanistic descriptions for glycosidases. In view of the importance of developing improved anti-influenza drugs, simulations of sialidases that considered both sialyl oxacarbenium ion and covalent sialyl-enzyme as possible intermediates could provide particular insight.
Original languageEnglish
Pages (from-to)1507-1514
Number of pages8
JournalPure and Applied Chemistry
Volume83
Issue number8
DOIs
Publication statusPublished - 2011

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Cations
Positive ions
Water
Free energy
Molecular dynamics
Ions
Molecules
Glycoside Hydrolases
Splines
Dynamic analysis
Enzymes
Atoms
Computer simulation
Pharmaceutical Preparations
Temperature

Cite this

Does glycosyl transfer involve an oxacarbenium intermediate? Computational simulation of the lifetime of the methoxymethyl cation in water. / Williams, Ian H; Ruiz-Pernia, J Javier; Tunon, Inaki.

In: Pure and Applied Chemistry, Vol. 83, No. 8, 2011, p. 1507-1514.

Research output: Contribution to journalArticle

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