STRUCTURE-BASED THERMODYNAMIC ANALYSIS OF HIV-1 PROTEASE INHIBITORS

A structural parametrization of the binding and folding energetics pre viously developed in this laboratory accounts quantitatively for the b inding of 13 HIV-1 protease inhibitors for which high-resolution struc tures are available (A77003, A78791, A76928, A74704, A76889, VX478, SB 203386, SB203238, SB206343, U100313, U89360, A98881, CGP53820). The bi nding free energies for the inhibitors are predicted with a standard d eviation of +/-1.1 kcal/mol or +/-10%. Furthermore, the formalism corr ectly predicts the observed change in inhibition constant for the comp lex of A77003 and the resistant protease mutant V82A, for which the hi gh-resolution structure is also available. The analysis presented here provides a structural mapping of the different contributions to the b inding energetics. Comparison of the binding map with the residue stab ility map indicates that the binding pocket in the protease molecule h as a dual character: half of the binding site is defined by the most s table region of the protein, while the other half is unstructured prio r to inhibitor or substrate binding. This characteristic of the bindin g site accentuates cooperative effects that permit mutations in distal residues to have a significant effect on binding affinity. These resu lts permit an initial assessment of the effects of mutations on the ac tivity of protease inhibitors.