title: NADH interactions with WT- and S94A-acyl carrier protein reductase from Mycobacterium tuberculosis: an ab initio study.
abstract: 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.
authors.affiliation: International School for Advanced Studies (SISSA) and Istituto Nazionale di Fisica della Materia, Trieste, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Pantano
authors.forename: Frank
authors.initials: F
authors.lastname: Alber
authors.forename: Doriano
authors.initials: D
authors.lastname: Lamba
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
mesh_terms: D000213:Acyl Carrier Protein / Q000378:metabolism; D000995:Antitubercular Agents / Q000378:metabolism; D001426:Bacterial Proteins; D024881:Drug Resistance, Bacterial; D007538:Isoniazid / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D008962:Models, Theoretical; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009243:NAD / Q000737:chemistry / Q000378:metabolism*; D010088:Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000213:Acyl Carrier Protein; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D009243:NAD; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; D007538:Isoniazid