Active-site dynamics of ASADH - A bacterial biosynthetic enzyme

Aspartate beta-semialdehyde dehydrogenase (ASADH) is an important enzyme in the synthesis of essential amino acids and therefore an attractive target for antibacterial, fungicidal, or herbicidal agents. The structure of the e nzyme has recently been determined by X-ray crystallography (Hadfield et al ., submitted for publication) both in the presence and absence of its cofac tor, NADP, and likely catalytic residues have been identified. Comparison o f the structures reveals both global and local conformational changes: In t he complex structure, the NADP binding domain moves closer to the substrate binding domain, and side chains involved in substrate binding are reorient ed. In addition, a loop region which is not observed in the structure of th e apo enzyme becomes ordered and is found close to the active site. To exam ine the structure of this loop in the native enzyme and to study the dynami cs and interactions at the active site, we performed molecular dynamics sim ulations of ASADH with a stochastic boundary technique. Multiple simulated annealing refinements against the crystallographic data were also performed to examine structural variability in the native and complexed enzyme. The results shed light on the active-site structure and dynamics of this import ant enzyme. (C) 1999 John Wiley & Sons, Inc. Int J Quant Chem 73: 137-146, 1999.