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


Reference:

Williams, I. H., Pernia, J. J. R. and Tunon, I., 2011. Does glycosyl transfer involve an oxacarbenium intermediate? Computational simulation of the lifetime of the methoxymethyl cation in water. Pure and Applied Chemistry, 83 (8), pp. 1507-1514.

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Official URL:

http://dx.doi.org/10.1351/PAC-CON-10-10-12

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.

Details

Item Type Articles
CreatorsWilliams, I. H., Pernia, J. J. R. and Tunon, I.
DOI10.1351/PAC-CON-10-10-12
DepartmentsFaculty of Science > Chemistry
RefereedYes
StatusPublished
ID Code25334

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