Exploring the concerted mechanistic pathway for HIV-1 PR—substrate revealed by umbrella sampling simulation

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dc.contributor.authorZainab K. Sanusi
dc.contributor.authorMonsurat M. Lawal
dc.contributor.authorPancham Lal. Gupta
dc.contributor.authorThavendran Govender
dc.contributor.authorSooraj Baijnath
dc.contributor.authorTricia Naicker
dc.contributor.authorGlenn E. M. Maguire
dc.contributor.authorBahareh Honarparvar
dc.contributor.authorAdrian E. Roitberg
dc.contributor.authorHendrik G. Kruger
dc.date.accessioned2023-05-17T13:36:11Z
dc.date.available2023-05-17T13:36:11Z
dc.date.issued2020-10-19
dc.descriptionExploring the concerted mechanistic pathway for HIV-1 PR—substrate revealed by umbrella sampling simulation
dc.description.abstractHIV-1 protease (HIV-1 PR) is an essential enzyme for the replication process of its virus, and therefore considered an important target for the development of drugs against the acquired immunodeficiency syndrome (AIDS). Our previous study shows that the catalytic mechanism of subtype B/C-SA HIV-1 PR follows a one-step concerted acyclic hydrolysis reaction process using a two-layered ONIOM B3LYP/6- 31þþG(d,p) method. This present work is aimed at exploring the proposed mechanism of the proteolysis catalyzed by HIV-1 PR and to ensure our proposed mechanism is not an artefact of a single theoretical technique. Hence, we present umbrella sampling method that is suitable for calculating potential mean force (PMF) for non-covalent ligand/substrate-enzyme association/dissociation interactions which provide thermodynamic details for molecular recognition. The free activation energy results were computed in terms of PMF analysis within the hybrid QM(DFTB)/MM approach. The theoretical findings suggest that the proposed mechanism corresponds in principle with experimental data. Given our observations, we suggest that the QM/MM MD method can be used as a reliable computational technique to rationalize lead compounds against specific targets such as the HIV-1 protease.
dc.identifier.citation: Zainab K. Sanusi, Monsurat M. Lawal, Pancham Lal. Gupta, Thavendran Govender, Sooraj Baijnath, Tricia Naicker, Glenn E. M. Maguire, Bahareh Honarparvar, Adrian E. Roitberg & Hendrik G. Kruger (2022) Exploring the concerted mechanistic pathway for HIV-1 PR—substrate revealed by umbrella sampling simulation, Journal of Biomolecular Structure and Dynamics, 40:4, 1736-1747, DOI: 10.1080/07391102.2020.1832578
dc.identifier.issn1736–1747
dc.identifier.urihttps://uzspace.unizulu.ac.za/handle/10530/2324
dc.language.isoen
dc.publisherUniversity of Zululand
dc.titleExploring the concerted mechanistic pathway for HIV-1 PR—substrate revealed by umbrella sampling simulation
dc.typeArticle
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