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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Small Research Grants (R03)
Project #
5R03AA012753-02
Application #
6509390
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Salin, Marvin L
Project Start
2001-06-01
Project End
2003-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$73,925
Indirect Cost
Name
Carnegie-Mellon University
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Wymore, Troy; Hempel, John; Cho, Samuel S et al. (2004) Molecular recognition of aldehydes by aldehyde dehydrogenase and mechanism of nucleophile activation. Proteins 57:758-71
Wymore, Troy; Deerfield 2nd, David W; Field, Martin J et al. (2003) Initial catalytic events in class 3 aldehyde dehydrogenase: MM and QM/MM simulations. Chem Biol Interact 143-144:75-84