COMPUTATIONAL CHEMISTRY OF ALDEHYDE DEHYDROGENASES

Carnegie-Mellon University, Pittsburgh PA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. molecular dynamics aldehyde dehydrogenase metabolism 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 ALDH2, acetaldehyde in the Michaelis complex with ALDH, and the thioester intermediate state with molecular dynamics (MD) simulations. In addition, potential energy surfaces of key reaction steps of ALDH2 will be calculated using a quantum mechanical/molecular mechanical (QM/MM) method. These calculations will determine the structural and dynamics 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.