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Pure Appl. Chem., 2011, Vol. 83, No. 8, pp. 1507-1514

Published online 2011-04-04

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

Ian H. Williams1*, J. Javier Ruiz Pernía1 and Iñaki Tuñón2

1 Department of Chemistry, University of Bath, Bath, BA2 7AY, UK
2 Department of Chemistry, University of Valencia, 46100 Burjassot, Spain

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.