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Biophys. J. BioFAST: First Published May 20, 2005. doi:10.1529/biophysj.104.053512
© 2005 by the Biophysical Society.

A more recent version of this article appeared on August 1, 2005.
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BIOPHYSICAL THEORY AND MODELING

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

Evelyn Koeche Schroeder 1, Luiz Augusto Basso 1, Diógenes Santiago Santos 2 and Osmar Norberto de Souza 2*

1 Universidade Federal do Rio Grande do Sul
2 Pontifícia Universidade Católica do Rio Grande do Sul

* To whom correspondence should be addressed. E-mail: osmarns{at}inf.pucrs.br.

Submitted on October 5, 2004
Revised on December 20, 2004
Accepted on 9 May 2005


  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 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 co-factor within the NADH binding site. In order 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 (wt and mutants) were performed. Although very flexible, in the wt 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.

Key Words: InhA mutants, Mycobacterium tuberculosis, NADH, enoyl-ACP-reductase, enzyme-ligand affinity, molecular dynamics simulation




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Copyright © 2005 by the Biophysical Society.