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Concerted hydrolysis mechanism of HIV-1 natural substrate against subtypes B and C-SA PR: insight through molecular dynamics and hybrid QM/MM studies

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Abstract

It is well known that understanding the catalytic mechanism of HIV-1 PR is the rationale on which its inhibitors were developed; therefore, a better understanding of the mechanism of natural substrate hydrolysis is important. Herein, the reaction mechanism of HIV-1 natural substrates with subtypes B and common mutant in South Africa (subtype C-SA) protease were studied through transition state modelling, using a general acid–general base (GA–GB) one-step concerted process. The activation free energies of enzyme–substrate complexes were compared based on their rate of hydrolysis using a two-layered ONIOM (B3LYP/6-31++G(d,p):AMBER) method. We expanded our computational model to obtain a better understanding of the mechanism of hydrolysis as well as how the enzyme recognises or chooses the cleavage site of the scissile bonds. Using this model, a potential substrate-based inhibitor could be developed with better potency. The calculated activation energies of natural substrates in our previous study correlated well with experimental data. A similar trend was observed for the Gag and Gag-Pol natural substrates in the present work for both enzyme complexes except for the PR-RT substrate. Natural bond orbital (NBO) analysis was also applied to determine the extent of charge transfer within the QM part of both enzymes considered and the PR-RT natural substrate. The result of this study shows that the method can be utilized as a dependable computational technique to rationalize lead compounds against specific targets.

Graphical abstract: Concerted hydrolysis mechanism of HIV-1 natural substrate against subtypes B and C-SA PR: insight through molecular dynamics and hybrid QM/MM studies

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Supplementary files

Article information


Submitted
16 Oct 2019
Accepted
19 Dec 2019
First published
09 Jan 2020

Phys. Chem. Chem. Phys., 2020, Advance Article
Article type
Paper

Concerted hydrolysis mechanism of HIV-1 natural substrate against subtypes B and C-SA PR: insight through molecular dynamics and hybrid QM/MM studies

Z. K. Sanusi, M. M. Lawal, T. Govender, S. Baijnath, T. Naicker, G. E. M. Maguire, B. Honarparvar and H. G. Kruger, Phys. Chem. Chem. Phys., 2020, Advance Article , DOI: 10.1039/C9CP05639D

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