Shape Complementarity in Serine Protease-inhibitor Complexes Correlate to Inhibition Constants

Natural proteinaceous protease inhibitors inhibit through nonproductive binding to proteases and steric blockage of active sites. These complexes are among the most structurally complementary protein-protein interactions. To see if complementarity is correlated to activity, we scored the shape complementarity in 15 serine protease-inhibitor complexes through in silico docking and compared the scores against their reported inhibition constants (Ki). A statistically significant, moderate and positive correlation was observed between shape complementarity and Ki (R = 0.58; P = 0.023). We also analyzed other physicochemical factors involved in serine protease-inhibitor interactions for correlation, but no other factor was correlated to Ki. However, significant correlations were observed between hydrogen bonds and interface areas (R = 0.762; P = 0.0004); and between hydrophobic interactions and free energies of solvation (R = -0.634; P = 0.011).