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

Abstract

HIV-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/6-31++G(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.

Keywords:

• HIV-1 subtypes B and C-SA PR
• HIV-1 PR cleavage mechanism
• Umbrella sampling method
• Steered molecular dynamics (SMD)
• Natural substrates
• Activation free energy
• Concerted transition state

Acknowledgements

The authors thank the College of Health Sciences, University of KwaZulu-Natal, Asphen Pharmacare, Medical Research Council, and the National Research Foundation (all in South Africa) for financial support. The authors also acknowledge the University of Florida Research Computing for providing computational resources and support that contributed to the research results reported in this publication. GK thank AR for hosting ZS and ML at UF during the project. We are also grateful to the Centre for High-Performance Computing (www.chpc.ac.za) for computational resources.

Disclosure statement

The authors declare that they have no competing interests.