Direct dynamics calculations of reaction rate and kinetic isotope effects in enzyme catalysed reactions

Abstract

Direct dynamics calculations employing hybrid quantum mechanical and molecular mechanical (QM/MM) potentials and molecular dynamics simulation methods have been used to explore the important dynamic role that enzyme structure has on proton transfer in the C–H bond breakage of a methylamine substrate by methylamine dehydrogenase (MADH). Canonical variational transition state theory with optimised multidimensional tunnelling corrections has been used to predict deuterium kinetic isotope effects corresponding to a range of enzyme conformations and to show the importance of donor–acceptor separation, and transition state and product stabilisation within the active site. Large kinetic isotope effects can be predicted for proton transfer with both semi-empirical and ab initio electronic structure methods.