Investigating structure activity relationships in autoprocessing by HIV-1 protease

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Project Summary The long-term goal of this project is a detailed mechanistic understanding of the autoprocessing mechanism by which viral proteases cut themselves out of precursor polyproteins. Autoprocessing is critical to the life cycle of many viruses, but is poorly understood in part because the structure of protease in polyproteins is highly dynamic. In Aim 1, we will determine the potency of a panel of inhibitors for autoprocessing of HIV-1 protease. The results from this aim will provide a guide to understand the physical properties at different positions on inhibitors that govern binding. In Aim 2, we will use deep mutational scanning to determine how all possible point mutations in protease impact autoprocessing efficiency. The results from this aim will determine the physical requirements at each position in protease for autoprocessing. Together, these aims will provide a detailed understanding of the physical underpinnings of autoprocessing by HIV-1 protease.