Ritonavir and xk263 Binding-Unbinding with HIV-1 Protease: Pathways, Energy and Comparison

Abstract

Understanding non-covalent biomolecular recognition, which includes drug–protein bound states and their binding/unbinding processes, is of fundamental importance in chemistry, biology, and medicine. Fully revealing the factors that govern the binding/unbinding processes can further assist in designing drugs with desired binding kinetics. HIV protease (HIVp) plays an integral role in the HIV life cycle, so it is a prime target for drug therapy. HIVp has flexible flaps, and the binding pocket can be accessible by a ligand via various pathways. Comparing ligand association and dissociation pathways can help elucidate the ligand–protein interactions such as key residues directly involved in the interaction or specific protein conformations that determine the binding of a ligand under certain pathway(s). Here, we investigated the ligand unbinding process for a slow binder, ritonavir, and a fast binder, xk263, by using unbiased all-atom accelerated molecular dynamics (aMD) simulation with a re-seeding approach and an explicit solvent model. Using ritonavir-HIVp and xk263-HIVp ligand–protein systems as cases, we sampled multiple unbinding pathways for each ligand and observed that the two ligands preferred the same unbinding route. However, ritonavir required a greater HIVp motion to dissociate as compared with xk263, which can leave the binding pocket with little conformational change of HIVp. We also observed that ritonavir unbinding pathways involved residues which are associated with drug resistance and are distal from catalytic site. Analyzing HIVp conformations sampled during both ligand–protein binding and unbinding processes revealed significantly more overlapping HIVp conformations for ritonavir-HIVp rather than xk263-HIVp. However, many HIVp conformations are unique in xk263-HIVp unbinding processes. The findings are consistent with previous findings that xk263 prefers an induced-fit model for binding and unbinding, whereas ritonavir favors a conformation selection model. This study deepens our understanding of the dynamic process of ligand unbinding and provides insights into ligand–protein recognition mechanisms and drug discovery.

Comparative study of the unbinding process of some HTLV-1 protease inhibitors using unbiased molecular dynamics simulations

“…In some research, protonation is not applied or not mentioned, or in some research, protonation state is applied in chain A. As we wanted a more complete outcome, we used protonation separately in both chains [ 26 , 27 ]. So after preparing complexes, each catalytic Asp was considered separately as an ionization state based on the monoprotonated (mp) form of the catalytic dyad Asp32-Asp32′ in the active site [ 28 ].…”

Exploring the inhibition mechanism of SARS‐CoV‐2 main protease by ebselen: A molecular docking, molecular dynamics simulation and DFT approach

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Appraisal of evidence reliability and applicability of Paxlovid as treatment for SARS‐COV‐2 infection: A systematic review

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