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HARP: a database of structural impacts of systematic missense mutations in drug targets of Mycobacterium leprae

Vedithi, Sundeep Chaitanya; Malhotra, Sony; Skwark, Marcin J; Munir, Asma; Acebron-Garcia-De-Eulate, Marta; Waman, Vaishali P; Alsulami, Ali; ... Blundell, Tom L; + view all (2020) HARP: a database of structural impacts of systematic missense mutations in drug targets of Mycobacterium leprae. Computational and Structural Biotechnology Journal , 18 pp. 3692-3704. 10.1016/j.csbj.2020.11.013. Green open access

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Abstract

Computational Saturation Mutagenesis is an in-silico approach that employs systematic mutagenesis of each amino acid residue in the protein to all other amino acid types, and predicts changes in thermodynamic stability and affinity to the other subunits/protein counterparts, ligands and nucleic acid molecules. The data thus generated are useful in understanding the functional consequences of mutations in antimicrobial resistance phenotypes. In this study, we applied computational saturation mutagenesis to three important drug-targets in Mycobacterium leprae (M. leprae) for the drugs dapsone, rifampin and ofloxacin namely Dihydropteroate Synthase (DHPS), RNA Polymerase (RNAP) and DNA Gyrase (GYR), respectively. M. leprae causes leprosy and is an obligate intracellular bacillus with limited protein structural information associating mutations with phenotypic resistance outcomes in leprosy. Experimentally solved structures of DHPS, RNAP and GYR of M. leprae are not available in the Protein Data Bank, therefore, we modelled the structures of these proteins using template-based comparative modelling and introduced systematic mutations in each model generating 80,902 mutations and mutant structures for all the three proteins. Impacts of mutations on stability and protein-subunit, protein-ligand and protein-nucleic acid affinities were computed using various in-house developed and other published protein stability and affinity prediction software. A consensus impact was estimated for each mutation using qualitative scoring metrics for physicochemical properties and by a categorical grouping of stability and affinity predictions. We developed a web database named HARP (a database of Hansen's Disease Antimicrobial Resistance Profiles), which is accessible at the URL - https://harp-leprosy.org and provides the details to each of these predictions.

Type: Article
Title: HARP: a database of structural impacts of systematic missense mutations in drug targets of Mycobacterium leprae
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.csbj.2020.11.013
Publisher version: https://doi.org/10.1016/j.csbj.2020.11.013
Language: English
Additional information: ©2020 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Biotechnology & Applied Microbiology, Drug resistance, Mutations, Protein stability, Interatomic interactions, Mycobacterium leprae, Computational saturation mutagenesis, WEB SERVER, DIHYDROPTEROATE SYNTHASE, DAPSONE RESISTANCE, PROTEIN-SEQUENCE, LEPROSY PATIENTS, RIFAMPICIN, STABILITY, VISUALIZATION, EMERGENCE, PREDICT
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10161585
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