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Active‐site dynamics of ASADH—A bacterial biosynthetic enzyme
Author(s) -
Hadfield Andrea T.,
Mulholland Adrian J.
Publication year - 1999
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/(sici)1097-461x(1999)73:2<137::aid-qua8>3.0.co;2-q
Subject(s) - active site , chemistry , enzyme , molecular dynamics , stereochemistry , binding site , cofactor , substrate (aquarium) , oxidoreductase , protein structure , dehydrogenase , crystallography , biochemistry , computational chemistry , biology , ecology
Aspartate β‐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 enzyme has recently been determined by X‐ray crystallography (Hadfield et al., submitted for publication) both in the presence and absence of its cofactor, NADP, and likely catalytic residues have been identified. Comparison of the structures reveals both global and local conformational changes: In the complex structure, the NADP binding domain moves closer to the substrate binding domain, and side chains involved in substrate binding are reoriented. In addition, a loop region which is not observed in the structure of the apo enzyme becomes ordered and is found close to the active site. To examine the structure of this loop in the native enzyme and to study the dynamics and interactions at the active site, we performed molecular dynamics simulations 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 important enzyme. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 73: 137–146, 1999