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NADH interactions with WT‐ and S94A‐acyl carrier protein reductase from Mycobacterium tuberculosis: An ab initio study
Author(s) -
Pantano Sergio,
Alber Frank,
Lamba Doriano,
Carloni Paolo
Publication year - 2002
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.1177
Subject(s) - inha , chemistry , mycobacterium tuberculosis , mutant , ab initio , crystallography , hydrazide , mutant protein , protein structure , stereochemistry , biochemistry , tuberculosis , organic chemistry , medicine , pathology , gene
We present an ab initio molecular dynamics study of the complex between acyl carrier protein reductase InhA from M. tuberculosis and isonicotinic acid hydrazide‐NADH. We focus on wild‐type (WT) InhA and a mutant causing drug resistance (S94A) for which structural information is available (Rozwarski et al., 1998;279:98–102; Dessen et al., 1995;267:1638–1641). Our calculations suggest that the water‐mediated H‐bond interactions between Ser94 side chain and NADH, present in WT InhA X‐ray structure, can be lost during the dynamics. This conformational change is accompanied by a structural rearrangement of Gly14. The calculated structure of WT is rather similar to the X‐ray structure of the S94A mutant in terms of geometrical parameters and chemical bonding. Further evidence for the mobility of Ser94 is provided by a 1‐ns‐long classical molecular dynamics on the entire protein. The previously unrecognized high mobility of Ser94 can provide a rationale of the small change in free binding energies on passing from WT to S94A InhA. Proteins 2002;47:62–68. © 2002 Wiley‐Liss, Inc.