Molecular Dynamics Simulation of Aldehyde Dehydrogenase

Carnegie-Mellon University, Pittsburgh PA

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Abstract

The function of enzymes are determined by many interactions that can be hard to dissect experimentally and as such computer models that reproduce experiments can give atomic level details for such observables. These interactions are also important for the rational design of inhibitors of enzyme function. The goal of the proposed research is a detailed understanding of the catalytic mechanism of aldehyde dehydrogenase (ALDH) conversion of aldehyde to its corresponding carboxylic acid through the use of computational chemistry calculations. These calculations include examination of ground state structures of holo-form ALDH, benzaldehyde in the Michaelis-Menten complex with ALDH, and the thiohemiacetal intermediate state with molecular dynamics (MD) simulations. In addition, the potential energy surfaces of key reaction steps of ALDH will be calculated using a quantum mechanical/molecular mechanical (QM/MM) method. These calculations will determine the structural and dynamic roles that residues play in this catalytic reaction. Finally, by integrating these calculation results with those from sequence analysis and site-directed mutagenesis experiments, we intend to understand the molecular factors that influence all ALDHs.