Conformational changes in 2-trans-enoyl-ACP (CoA) reductase (InhA) from M. tuberculosis induced by an inorganic complex: A molecular dynamics simulation study

André L.P. Da Costa, Ivani Pauli, Márcio Dorn, Evelyn K. Schroeder, Chang Guo Zhan, Osmar Norberto De Souza

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13 Scopus citations


InhA, the NADH-dependent 2-trans-enoyl-ACP reductase enzyme from Mycobacterium tuberculosis (MTB), is involved in the biosynthesis of mycolic acids, the hallmark of mycobacterial cell wall. InhA has been shown to be the primary target of isoniazid (INH), one of the oldest synthetic antitubercular drugs. INH is a prodrug which is biologically activated by the MTB catalaseperoxidase KatG enzyme. The activation reaction promotes the formation of an isonicotinyl-NAD adduct which inhibits the InhA enzyme, resulting in reduction of mycolic acid biosynthesis. As a result of rational drug design efforts to design alternative drugs capable of inhibiting MTB's InhA, the inorganic complex pentacyano(isoniazid)ferrate(II) (PIF) was developed. PIF inhibited both wild-type and INH-resistant Ile21Val mutants of InhA and this inactivation did not require activation by KatG. Since no threedimensional structure of the InhA-PIF complex is available to confirm the binding mode and to assess the molecular interactions with the protein active site residues, here we report the results of molecular dynamics simulations of PIF interaction with InhA. We found that PIF strongly interacts with InhA and that these interactions lead to macromolecular instabilities reflected in the long time necessary for simulation convergence. These instabilities were mainly due to perturbation of the substrate binding loop, particularly the partial denaturation of helices α6 and α7. We were also able to correlate the changes in the SASAs of Trp residues with the recent spectrofluorimetric investigation of the InhA-PIF complex and confirm their suggestion that the changes in fluorescence are due to InhA conformational changes upon PIF binding. The InhA-PIF association is very strong in the first 20.0 ns, but becomes very week at the end of the simulation, suggesting that the PIF binding mode we simulated may not reflect that of the actual InhAPIF complex.

Original languageEnglish
Pages (from-to)1779-1790
Number of pages12
JournalJournal of Molecular Modeling
Issue number5
StatePublished - May 2012

Bibliographical note

Funding Information:
We would like to thank Luís Fernando Saraiva Macedo Timmers for his technical assistance. We thank the Laboratório de Alto Desempenho (LAD), at Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), for CPU time. This project was supported all or in part by grants from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and Ministério da Ciência e Tecnologia (MCT) – Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) – Departamento de Ciência e Tecnologia (DECIT), (Processes numbers 410505/2006-4, 554782/2008-1, 302641/2009-2, 551209/2010-0, 559917/2010-4) to Osmar Norberto de Souza and Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB) – CNPq to Prof. Diógenes Santiago Santos and Programa de Apoio a Núcleos de Excelência 2009/FAPERGS to Prof. Luiz Augusto Basso. André L. P. da Costa was partially supported by a CAPES M.Sc. scholarship. Ivani Pauli was supported by a CAPES M.Sc scholarship. Márcio Dorn was supported by a CNPq M.Sc. scholarship. Osmar Norberto de Souza is a CNPq Research Fellow.


  • Conformational changes
  • FAS-II pathway
  • InhA
  • Molecular dynamics simulations
  • Mycobacterium tuberculosis
  • Pentacyano(isoniazid)ferrate(II)

ASJC Scopus subject areas

  • Catalysis
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Computational Theory and Mathematics
  • Inorganic Chemistry


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