Molecular Dynamics Assisted Mechanistic Study of Isoniazid-Resistance against Mycobacterium tuberculosis InhA

Examination of InhA mutants I16T, I21V, I47T, S94A, and I95P showed that direct and water mediated H-bond interactions between NADH and binding site residues reduced drastically. It allowed conformational flexibility to NADH, particularly at the pyrophosphate region, leading to weakening of its bind...

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Main Authors:	Kumar, Vivek, Sobhia, M. Elizabeth
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682841/

id	pubmed-4682841
recordtype	oai_dc
spelling	pubmed-46828412015-12-31 Molecular Dynamics Assisted Mechanistic Study of Isoniazid-Resistance against Mycobacterium tuberculosis InhA Kumar, Vivek Sobhia, M. Elizabeth Research Article Examination of InhA mutants I16T, I21V, I47T, S94A, and I95P showed that direct and water mediated H-bond interactions between NADH and binding site residues reduced drastically. It allowed conformational flexibility to NADH, particularly at the pyrophosphate region, leading to weakening of its binding at dinucleotide binding site. The highly scattered distribution of pyrophosphate dihedral angles and chi1 side chain dihedral angles of corresponding active site residues therein confirmed weak bonding between InhA and NADH. The average direct and water mediated bridged H-bond interactions between NADH and mutants were observed weaker as compared to wild type. Further, estimated NADH binding free energy in mutants supported the observed weakening of InhA-NADH interactions. Similarly, per residue contribution to NADH binding was also found little less as compared to corresponding residues in wild type. This investigation clearly depicted and supported the effect of mutations on NADH binding and can be accounted for isoniazid resistance as suggested by previous biochemical and mutagenic studies. Further, structural analysis of InhA provided the crucial points to enhance the NADH binding affinity towards InhA mutants in the presence of direct InhA inhibitors to combat isoniazid drug resistance. This combination could be a potential alternative for treatment of drug resistant tuberculosis. Public Library of Science 2015-12-14 /pmc/articles/PMC4682841/ /pubmed/26658674 http://dx.doi.org/10.1371/journal.pone.0144635 Text en © 2015 Kumar, Sobhia http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kumar, Vivek Sobhia, M. Elizabeth
spellingShingle	Kumar, Vivek Sobhia, M. Elizabeth Molecular Dynamics Assisted Mechanistic Study of Isoniazid-Resistance against Mycobacterium tuberculosis InhA
author_facet	Kumar, Vivek Sobhia, M. Elizabeth
author_sort	Kumar, Vivek
title	Molecular Dynamics Assisted Mechanistic Study of Isoniazid-Resistance against Mycobacterium tuberculosis InhA
title_short	Molecular Dynamics Assisted Mechanistic Study of Isoniazid-Resistance against Mycobacterium tuberculosis InhA
title_full	Molecular Dynamics Assisted Mechanistic Study of Isoniazid-Resistance against Mycobacterium tuberculosis InhA
title_fullStr	Molecular Dynamics Assisted Mechanistic Study of Isoniazid-Resistance against Mycobacterium tuberculosis InhA
title_full_unstemmed	Molecular Dynamics Assisted Mechanistic Study of Isoniazid-Resistance against Mycobacterium tuberculosis InhA
title_sort	molecular dynamics assisted mechanistic study of isoniazid-resistance against mycobacterium tuberculosis inha
description	Examination of InhA mutants I16T, I21V, I47T, S94A, and I95P showed that direct and water mediated H-bond interactions between NADH and binding site residues reduced drastically. It allowed conformational flexibility to NADH, particularly at the pyrophosphate region, leading to weakening of its binding at dinucleotide binding site. The highly scattered distribution of pyrophosphate dihedral angles and chi1 side chain dihedral angles of corresponding active site residues therein confirmed weak bonding between InhA and NADH. The average direct and water mediated bridged H-bond interactions between NADH and mutants were observed weaker as compared to wild type. Further, estimated NADH binding free energy in mutants supported the observed weakening of InhA-NADH interactions. Similarly, per residue contribution to NADH binding was also found little less as compared to corresponding residues in wild type. This investigation clearly depicted and supported the effect of mutations on NADH binding and can be accounted for isoniazid resistance as suggested by previous biochemical and mutagenic studies. Further, structural analysis of InhA provided the crucial points to enhance the NADH binding affinity towards InhA mutants in the presence of direct InhA inhibitors to combat isoniazid drug resistance. This combination could be a potential alternative for treatment of drug resistant tuberculosis.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682841/
_version_	1613513928099233792

Molecular Dynamics Assisted Mechanistic Study of Isoniazid-Resistance against Mycobacterium tuberculosis InhA

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