NADH interactions with WT- and S94A-acyl carrier protein reductase from Mycobacterium tuberculosis: an ab initio study.

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.