Quantitative symmetry in structure-activity correlations: The near C-2 symmetry of inhibitor/HIV protease complexes

We studied the way in which the binding of inhibitors of human immunodefici ency virus (HIV) protease causes the protein to deviate from its original C -2 symmetric structure. We extended to C-2 symmetry our findings that quant itative chirality is a useful, predictive parameter in enzymatic structure- activity correlations (J. Am. Chem. Sec. 1998, 120, 6152-6159). We provide a quantitative assessment of this deviation, the degree of C-2-ness, S(C-2) , by employing the continuous symmetry measures methodology. The data analy zed was for a group of 13 inhibitor/protease complexes, for which the struc tures and the binding energies are known. S(C-2) was determined for the inh ibitors before and after binding, for each pair of amino acids of the prote in, and for the whole protein complexes. We were able to track the spreadin g of the C-2 distortion throughout the protein to various zones. Maps of is o-symmetry value proved to be a powerful descriptive tool for protein struc ture-deviation visualization. The main findings are the following: (i) For most inhibitors, the active site imposes its C-2 symmetry On the bound inhi bitor, rendering it more C-2 symmetric than its free form and confirming th e picture of enzymes as mechanical devices. (ii) The binding energy of the inhibitors correlates with this imposed C-2 symmetry change: the smaller th e symmetry change, the better the inhibition. (iii) Analysis of the enzyme' s mutant strain V82A (raised against the inhibitors) shows that it has "lea rned" to cope better with an inhibitor by "following" this symmetry/binding energy correlation. (iv) Symmetry deviations occur in the protein upon bin ding at remote zones from the active site. Despite variations in the detail s of these deviations for the different HIV protease/inhibitor complexes, t he protein as a whole responds to the various inhibitors with a very simila r C-2 symmetry change: a global symmetry-well for this protein, has been id entified.