title: Sliding Clamp of DNA Polymerase III as a Drug Target for TB Therapy: Comprehensive Conformational and Binding Analysis from Molecular Dynamic Simulations.
abstract: Tuberculosis, caused by Mycobacterium tuberculosis, is one of the most common causes of death in the world. Mycobacterium tuberculosis -sliding clamp is a protein essential for many important DNA transactions including replication and DNA repair proteins, thus, a potential drug target for tuberculosis. Further investigation is needed in understanding DNA polymerase sliding clamp structure, especially from a computational perspective. In this study, we employ a wide-range of comparative molecular dynamic analyses on two systems: Mycobacterium tuberculosis - sliding clamp enzyme in its apo and bound form. The results reported in this study shows apo conformation to be less stable, as compared to bound conformation with an average radius of gyration of 25.812 and 25.459 Å, respectively. This was further supported by root mean square fluctuation, where an apo enzyme showed a higher degree of flexibility. However, the presence of the ligand lowers radius of gyration and root mean square fluctuation and also leads to an existence of negative correlated motions. Principal component analysis further justifies the same findings, whereby the apo enzyme exhibits a higher fluctuation compared to the bound complex. In addition, a stable 310helix located at the binding site appears to be unstable in the presence of the ligand. Hence, it is possible that the binding of the ligand may have caused a rearrangement of the structure, leading to a change in the unwinding of 310helix. Findings reported in this study further enhance the understanding of Mycobacterium tuberculosis -DnaN and also give a lead to the development of potent tuberculosis drugs.
authors.affiliation: Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa.
authors.forename: Kgothatso E
authors.initials: KE
authors.lastname: Machaba
authors.affiliation: Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa.
authors.forename: Favorite N
authors.initials: FN
authors.lastname: Cele
authors.affiliation: Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa.
authors.forename: Ndumiso N
authors.initials: NN
authors.lastname: Mhlongo
authors.affiliation: Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa. soliman@ukzn.ac.za.
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001665:Binding Sites; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D025341:Principal Component Analysis; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D004258:DNA Polymerase III
keywords: MD simulation; Post-dynamics analysis; TB sliding clamp