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

Abstract

Hybrid quantum mechanical and molecular mechanical (QM/MM) methods are used to estimate the kinetic isotope effects (KIEs) for the 1,2 hydride shift reaction of xylose isomerase. Semiclassical transition-state theory with multidimensional tunnelling corrections are evaluated with both semiempirical and ab initio density functional hybrid methods for the study of enzyme catalysis. As part of the study, a link atom and a modified localised self-consistent-field method are assessed to represent the QM and MM covalent interface region. We have shown for some model systems that although the bond orbital method can be adjusted to perform better than the link atom method by using auxiliary density basis functions or by charge scaling, in general the link atom method performs as well. Several QM/MM models are used to calculate the xylose isomerase potential-energy surface and the importance of tunnelling for the KIEs beyond the Wigner correction is demonstrated.