Adaptability and flexibility of HIV‐1 protease

Even though more than 200 three‐dimensional structures of HIV‐1 protease complexed to a variety of inhibitors are available in the Protein Data Bank; very few structures of unliganded protein have been determined. We have recently solved structures of unliganded HIV‐1 protease tethered dimer mutants to resolutions of 1.9 Å and 2.1 Å, and have found that the flaps assume closed‐flap conformation even in the absence of any bound ligand. We report comparison of the unliganded closed‐flap structure with structures of HIV‐1 protease inhibitor complexes with a view to accurately identifying structural changes that the ligand can induce on binding to HIV‐1 protease in the crystal. These studies reveal that the least flexible region present in the active site of HIV‐1 protease need not also be the least adaptable to external stress, thus highlighting the conceptual difference between flexibility and adaptability of proteins in general.