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| Ian Williams, University of Bath |
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Ian Williams obtained B.Sc. (1974) and Ph.D. (1978) degrees at the University of Sheffield. His doctoral research, under the supervision of James McKenna, concerned non-potential-energy contributions to organic reactivity. He spent two postdoctoral years at the University of Kansas performing quantum-chemical investigations of catalytic mechanisms with Professors Dick Schowen and Gerry Maggiora. Returning to the UK in 1980, he took up a Royal Society Pickering Research Fellowship at the University of Cambridge for independent research into theoretical modelling of organic reaction mechanisms. In 1985 he moved to the University of Bristol to continue his research in this area as a SERC Advanced Fellow. Despite having spent the preceding nine years in theoretical chemistry departments, he was appointed to a lectureship in organic chemistry at the University of Bath in 1989. Since then he has continued to teach physical organic chemistry to undergraduate students at all levels while pursuing research in computational chemistry. He was promoted to Reader in 1991 and Professor in 1995.
His research interests have spanned a wide range of topics in chemical reactivity, from atmospheric chemistry to molecular enzymology, but with the common theme of seeking to understand the properties and behaviour of transition states. In recent years he has collaborated closely with the group of Vicente Moliner in Castellón, Spain, where he spent a period of sabbatical leave in 2004, on computational modelling of enzyme mechanisms using hybrid quantum-mechanical/molecular-mechanical methods. Current interests concern the reactivity of alpha-lactones, catalysis by titanium complexes, glycoside hydrolysis mechanisms, and isotope effects in aliphatic nucleophilic substitution in solution. He is Chair of the Theoretical Chemistry Group of the Royal Society of Chemistry, a member of the Management Committee of the UK National Service for Computational Chemistry Software, the UK representative on the European Computational Chemistry Working Party, and he recently organised an international conference in Bath on the subject of isotope effects.
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Kinetic isotope effects for enzyme-catalysed methyl transfer
Ian H. Williams, Department of Chemistry, University of Bath, BA2 7AY Bath, United Kingdom
Experimentally, the secondary aplha-deuterium kinetic isotope effect (KIE) for methyl transfer catalyzed by catechol-O-methyltransferase (COMT), is much more inverse than for an uncatalyzed reaction in solution; this was previously interpreted to mean a tighter SN2 transition state (TS) for the COMT-catalyzed reaction than for the non-enzymic reaction. KIEs computed by a hybrid AM1/TIP3P/CHARMM method for the reaction of S-adenosylmethionine with catecholate anion in water and catalysed by COMT are in accord with experiment but do not support the compression hypothesis. A detailed analysis of the origin of these KIEs will be presented with a discussion of their implications. The terms "tight" and "loose" are often taken as geometrical descriptors of TSs but may equally describe stiffness as expressed by force constants. Care should be exercised in interpretation of KIEs as measures of TS structure, particularly if this information would be used for the design of TS analogues as inhibitors.
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