Ian Williams and colleagues at the University of Bath, UK, have demonstrated that kinetic isotope effects (KIEs) for a prototypical S­_N­2 methyl transfer in solution, and in an enzyme active site, show significant variations in magnitude owing to thermally-induced structural fluctuations.  

Williams' team have shown that thermal fluctuations must be taken into account to properly reproduce experimental KIE values, as different families of reactant-state conformers yield different KIE values.  

Using hybrid quantum-mechanics/molecular mechanics (QM/MM) calculations this concept discloses that an ensemble-averaging of KIE is necessary to produce data featuring quantitative experimental accuracy.

'These results represent a proof of concept; their quantitative accuracy may be improved by more expensive simulations using higher-level quantum-chemical methodologies in the future,' said Williams.

Michael Brown