Quantum mechanical/molecular mechanical methods and the study of kinetic isotope effects: modelling the covalent junction region and application to the enzyme xylose isomerase

Hybrid quantum mechanical and molecular mechanical(QM/MM) methods are used to estimate the kinetic isotope effects (KIEs) for the 1,2 hydride shift re action of xylose isomerase. Semiclassical transition-state theory with mult idimensional tunnelling corrections are evaluated with both semiempirical a nd ab initio density functional hybrid methods for the study of enzyme cata lysis. As part of the study, a link atom and a modified localised self-cons istent-yield method are assessed to represent the QM and MM covalent interf ace region. We have shown for some model systems that although the bond orb ital method can be adjusted to perform better than the link atom method by using auxiliary density basis functions or by charge scaling, in general th e link atom method performs as well. Several QM/MM models are used to calcu late the xylose isomerase potential-energy surface and the importance of tu nnelling for the KIEs beyond the Wigner correction is demonstrated.