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Human Immunodeficiency Virus (HIV) is a latent virus which attacks the immune system. Inhibitors disrupting HIV‐1 protease, a reproductive enzyme of the HIV virus, are a vital part of the cocktail of drugs necessary for treatment. Protease often accumulates mutations which do not affect enzyme function yet repel the inhibitor. New protease inhibitors (PI), engineered to fit within the substrate envelope, approximate the structure of the protease’s natural substrates. This approach limits the inhibitor’s contact with enzyme moieties that can cause resistance. Saquinavir is an outdated PI which protrudes beyond the substrate envelope at several locations. When HIV‐1 protease at mutations Gly48Val, Ile84Val, or Val82Ala occur, the drug becomes completely ineffective. Darunavir, a modern PI which fits almost perfectly within the substrate envelope, binds to the enzyme 1000 times more tightly than Saquinavir. Seven enzyme mutations must accumulate to repel this inhibitor completely. Protease residues with the potential to confer resistance to Darunavir include Val32, Ile47, Ile50, and Ile84. The Snyder High School SMART Team has designed two models contrasting the interactions of two PIs, Saquinavir and Darunavir, with HIV‐1 protease. Using Jmol modeling software and 3D printing technology, the team render protease residues and inhibitor molecules to highlight similarities and differences between the drugs, thus presenting specific HIV‐1 protease structure‐function relationships. Understanding the molecular basis of protease resistance is critical to developing effective drugs for treatment of HIV and other diseases. Continued research on the structure and function of protease‐PI interactions may allow researchers to innovate more effective therapies.

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