Speaker
Description
ABSTRACT:
Introduction and literature review
One infectious disease that has had both a profound health and cultural impact on the human race in recent decades is the Acquired Immune Deficiency Syndrome (AIDS) caused by Human Immunodeficiency Virus (HIV). A major breakthrough in the treatment of HIV-1 is the use of drugs inhibiting specific enzymes necessary for the replication of the virus. Among these enzymes is HIV-1 protease (PR), which is an important degrading enzyme necessary for the proteolytic cleavage of the Gag and Gag-Pol polyproteins, required for the development of mature virion proteins. The mechanism of action of the HIV-1 PR on the proteolysis of these polyproteins has been a subject of research over the past three decades.
Method
In this study, the one-step concerted catalytic mechanism of HIV-1 PR hydrolysis of a natural substrate was studied using a hybrid quantum mechanics/molecular mechanics (QM/MM; ONIOM) method. The mechanism is a general acid-base model having both catalytic aspartate group participating and water molecule attacking the natural substrate synchronously.
Results and discussion
Three different pathways were obtained; a concerted acyclic TS path, a concerted 6-membered cyclic TS model and another 6-membered ring TS mechanistic 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 obtained activation free energies are comparable to experimentally derived data of 15.69 kcal mol-1.
Conclusion
The outcome of the present work provides a plausible theoretical benchmark for the concerted enzymatic mechanism of HIV-1 PR.
KEYWORDS: HIV-1 PR, Natural substrate, Concerted mechanism, Transition state, ONIOM.
Presenter Biography
Monsurat M. Lawal obtained a master of medical science degree in pharmaceutical chemistry
under the supervision of Gert Kruger and Bahareh Honarparvar in 2016 having exploring organic
reactions using quantum mechanics methods. She is currently a PhD student at the Catalysis and
Peptide Research Unit (CPRU), University of KwaZulu-Natal. Her research focus is on HIV-1
protease mechanism, cyclic transition state modelling and advanced computational methods.
