Format

Send to

Choose Destination
Biophys J. 2005 Aug;89(2):876-84. Epub 2005 May 20.

Molecular dynamics simulation studies of the wild-type, I21V, and I16T mutants of isoniazid-resistant Mycobacterium tuberculosis enoyl reductase (InhA) in complex with NADH: toward the understanding of NADH-InhA different affinities.

Author information

1
Laboratório de Bioinformática, Modelagem e Simulação de Biossistemas-LABIO, PPGCC, Faculdade de Informática, PUCRS, Porto Alegre, RS, Brazil.

Abstract

The increasing prevalence of tuberculosis in many areas of the world, associated with the rise in drug-resistant Mycobacterium tuberculosis (MTB) strains, presents a major threat to global health. InhA, the enoyl-ACP reductase from MTB, catalyzes the nicotinamide adenine dinucleotide (NADH)-dependent reduction of long-chain trans-2-enoyl-ACP fatty acids, an intermediate in mycolic acid biosynthesis. Mutations in the structural gene for InhA are associated with isoniazid resistance in vivo due to a reduced affinity for NADH, suggesting that the mechanism of drug resistance may be related to specific interactions between enzyme and cofactor within the NADH binding site. To compare the molecular events underlying ligand affinity in the wild-type, I21V, and I16T mutant enzymes and to identify the molecular aspects related to resistance, molecular dynamics simulations of fully solvated NADH-InhA (wild-type and mutants) were performed. Although very flexible, in the wild-type InhA-NADH complex, the NADH molecule keeps its extended conformation firmly bound to the enzyme's binding site. In the mutant complexes, the NADH pyrophosphate moiety undergoes considerable conformational changes, reducing its interactions with its binding site and probably indicating the initial phase of ligand expulsion from the cavity. This study should contribute to our understanding of specific molecular mechanisms of drug resistance, which is central to the design of more potent antimycobacterial agents for controlling tuberculosis.

PMID:
15908576
PMCID:
PMC1366637
DOI:
10.1529/biophysj.104.053512
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center