Unraveling the concerted catalytic mechanism of the human immunodeficiency virus type 1 (HIV-1) protease: a hybrid QM/MM study


We give an account of a one-step concerted catalytic mechanism of HIV-1 protease (PR) hydrolysis of its natural substrate using a hybrid QM/MM method. The mechanism is a general acid–base model having both catalytic aspartate groups participating and a water molecule attacking the natural substrate synchronously. Three different pathways were investigated: a concerted acyclic transition state (TS) mechanistic route, a concerted 6-membered cyclic TS process involving one water molecule, and another 6-membered ring TS pathway involving two water molecules. Activation free energies of approximately 15.2 and 16.6 kcal mol−1 were obtained for both concerted acyclic and the other possible reaction pathway involving two water molecules in the active site, respectively. The activation free energies are comparable to experimentally derived data of 15.69 kcal mol−1. The outcome of the present work provides a plausible theoretical benchmark for the concerted enzymatic mechanism of HIV-1 PR and can be applied to related enzymatic processes.

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We are grateful to the Centre for High Performance Computing (www.chpc.ac.za) for computational resources.


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 the financial support.

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Correspondence to Hendrik G. Kruger.

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Proposed concerted scheme based on experimental report, 3D pictorial representation of the 6-membered cyclic TSs and the PDB formats of the ONIOM output files for the TS structures are available here.


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Lawal, M.M., Sanusi, Z.K., Govender, T. et al. Unraveling the concerted catalytic mechanism of the human immunodeficiency virus type 1 (HIV-1) protease: a hybrid QM/MM study. Struct Chem 30, 409–417 (2019). https://doi.org/10.1007/s11224-018-1251-9

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  • HIV-1 protease
  • Natural substrate
  • QM/MM (Our own N-layered Integrated molecular Orbital and molecular Mechanics ONIOM) method
  • Concerted transition states
  • Catalytic mechanism