<br/>Due to the high mutation rate caused by reverse transcription and rapid replication process, cross drug resistance has been a key obstacle in drug development for human immunodeficiency virus (HIV). HIV protease (HIVp) plays an integral role in its life cycle which makes it a prime target for drug therapy and compounds bind with longer residence time to HIVp may help to prevent drug resistance because pharmacological activity upholds when a drug is in bound-state with the target protein. Fully understanding the factors that govern a long or short residence time can assist us design drugs with desired binding kinetics. Here, we investigated ligand dissociation process for a slow binder, ritonavir, and a fast binder, xk263, by using unbiased all-atom accelerated molecular dynamics (aMD) simulation with reseeding approach and an explicit solvent model. Using ritonavir-HIVp and xk263-HIVp ligand-protein system as cases, we observed that these two ligands preferred same unbinding route. Moreover, ritonavir required larger HIVp motion to dissociate compared to xk263 dissociation process since xk263 can leave binding pocket without observable conformational change of HIVp. In addition, ritonavir formed more hydrogen bonds with multiple residues of HIVp. In contrast, hydrogen bonding between xk263 and HIVp was majorly restricted to Asp25, Asp124, Ile50 and Ile149. K-mean clustering on combined trajectory of ligand-protein association and dissociation revealed common HIVp conformations during ligand binding and unbinding. This study deepens our understanding of the dynamic process of ligand dissociation and provides insights into ligand-protein interaction and drug discovery.

Examining ligand-HIV protease dissociation: Pathway, energy, flexibility, and comparison with association processes

2019 Fall National Meeting

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