Investigation of protein-ligand binding motions through protein conformational morphing and clustering of cytochrome bc1-aa3 super complex

Sindhu, T and Rajamanikandan, S and Jeyakanthan, J and Pal, D (2023) Investigation of protein-ligand binding motions through protein conformational morphing and clustering of cytochrome bc1-aa3 super complex. In: Journal of Molecular Graphics and Modelling, 118 .

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Abstract

Cytochrome b (QcrB) is considered an essential subunit in the electron transport chain that coordinates the action of the entire cytochrome bc1 oxidase. It has been identified as an attractive drug target for a new promising clinical candidate Q203 that depletes the intracellular ATP levels in the bacterium, Mycobacterium tuberculosis. However, single point polymorphism (T313A/I) near the quinol oxidation site of QcrB developed resistance to Q203. In the present study, we analyze the structural changes and drug-resistance mechanism of QcrB due to the point mutation in detail through conformational morphing and molecular docking studies. By morphing, we generated conformers between the open and closed state of the electron transporting cytochrome bc1-aa3 super complex. We clustered them to identify four intermediate structures and relevant intra- and intermolecular motions that may be of functional relevance, especially the binding of Q203 in wild and mutant QcrB intermediate structures and their alteration in developing drug resistance. The difference in the binding score and hydrogen bond interactions between Q203 and the wild-type and mutant intermediate structures of QcrB from molecular docking studies showed that the point mutation T313A severely affected the binding affinity of the candidate drug. Together, the findings provide an in-depth understanding of QcrB inhibition in different conformations, including closed, intermediate, and open states of cytochrome bc1-aa3 super complex in Mycobacterium tuberculosis at the atomic level. We also obtain insights for designing QcrB and cytochrome bc1-aa3 inhibitors as potential therapeutics that may combat drug resistance in tuberculosis.

Item Type:	Journal Article
Publication:	Journal of Molecular Graphics and Modelling
Publisher:	Elsevier Inc.
Additional Information:	The copyright for this article belongs to Elsevier Inc.
Keywords:	Binding energy; Electron transport properties; Hydrogen bonds; Molecular modeling; Polymorphism; Tubes (components), 1-aa3 super complex; Bc; Clusterings; Drug-resistance; Intermediate structures; Morphing; Protein morphing; Q203; Qcrb; Tuberculosis, Proteins, cytochrome c oxidase; telacebec; tuberculostatic agent; ubiquinol cytochrome c reductase, Article; binding affinity; cluster analysis; conformational transition; DNA polymorphism; drug binding site; drug mechanism; drug structure; electron transport; hydrogen bond; ligand binding; molecular docking; molecular dynamics; Mycobacterium tuberculosis; point mutation; protein conformation; quantitative analysis; tautomer; tuberculosis
Department/Centre:	Division of Interdisciplinary Sciences > Computational and Data Sciences
Date Deposited:	27 Oct 2022 09:07
Last Modified:	27 Oct 2022 09:07
URI:	https://eprints.iisc.ac.in/id/eprint/77612

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