Computational Enzymology at the NRBSC involves developing and applying computational methods to quantitatively describe the mechanism of substrate binding to enzymes and their subsequent reactions. The methods that we employ involve high-level Quantum Mechanical (QM) calculations on small model systems, molecular dynamics simulations that employ molecular mechanical (MM) force fields and QM/MM potentials, as well as sequence-based bioinformatics methods.
We are currently focusing on examining the hydride transfer mechanism in several classes of ALDH. The hydride transfer reaction in this enzyme may originate from a very unstable thioacyl intermediate or possibly involve concerted proton transfer events. Which of these two mechanisms is correct greatly affects the interpretation of structure-function relationships in this enzyme and may offer an atomic rationale for various metabolic diseases. Proton and hydride quantum dynamical effects (tunneling) may also play a role.