PROTEIN-BINDING VERSUS PROTEIN-FOLDING - THE ROLE OF HYDROPHILIC BRIDGES IN PROTEIN ASSOCIATIONS

The role of hydrophilic bridges between charged, or polar, atoms in pr otein associations has been examined from two perspectives. First, sta tistical analysis has been carried out on 21 data sets to determine th e relationship between the binding free energy and the structure of th e protein complexes. We find that the number of hydrophilic bridges ac ross the binding interface shows a strong positive correlation with th e free energy; second, the electrostatic contribution of salt bridges to binding has been assessed by a continuum electrostatics calculation . In contrast to protein folding, we find that salt bridges across the binding interface can significantly stabilize complexes in some cases . The different contributions of hydrophilic bridges to folding and to binding arise from the different environments to which the involved h ydrophilic groups are exposed before and after the bridges are formed. These groups are more solvated in a denatured protein before folding than on the surface of the combining proteins before binding. After bi nding, they are buried in an environment whose residual composition ca n be much more hydrophilic than the one after folding. As a result, th e desolvation cost of a hydrophilic pair is lower, and the favorable i nteractions between the hydrophilic pair and its surrounding residues are generally stronger in binding than in folding. These results compl ement our recent finding that while hydrophobic effect in protein-prot ein interfaces is significant, it is not as strong as that observed in the interior of monomers. Taken together, these studies suggest that while the types of forces in protein-protein interaction and in protei n folding are similar, their relative contributions differ. Hence, ass ociation of protein monomers which do not undergo significant conforma tional change upon binding differs from protein folding, implying that conclusions (e.g. statistics, energetics) drawn from investigating fo lding may not apply directly to binding, and vice versa. (C) 1997 Acad emic Press Limited