FLEXIBILITY AND FUNCTION IN HIV-1 PROTEASE

HIV protease is a homodimeric protein whose activity is essential to v iral function. We have investigated the molecular dynamics of the HIV protease, thought to be important for proteinase function, bound to hi gh affinity inhibitors using NMR techniques. Analysis of N-15 spin ref axation parameters, of all but 13 backbone amide sites, reveals the pr esence of significant internal motions of the protein backbone. In par ticular, the flaps that cover the proteins active site of the protein have terminal loops that undergo large aCnpIitude motions on the ps to ns time scale, while the tips of the flaps undergo a conformational e xchange on the mu s time scale. This enforces the idea that the flaps of the proteinase are flexible structures that facilitate function by permitting substrate access to and product release from the active sit e of the enzyme.