Protein Binding Hot Spots

Areas of proteins ripe for protein-protein interactions, such as those that activate or inhibit activity, might be found by looking for disrupted solvent hydrogen-bond networks, according to modeling work by Ariel Fernández of the Argentine Institute of Mathematics and the University of Wisconsin’s Morgridge Institute for Research (Phys. Rev. Lett., DOI: 10.1103/physrevlett.108.188102). Computational scientists have historically tried to predict protein-protein associations by looking for shape complementarity or pairwise polar interactions. Fernández, in contrast, looked for areas around proteins where water molecules form fewer than four hydrogen bonds with their neighbors. Solvent hydrogen-bond networks normally drop off near proteins, but Fernández was able to identify hot spots with increased network disruption that correlated with known interactions between eight sets of protein pairs. “Protein structure—the shape as well as the chemical composition of the surface—can make certain water molecules very miserable,” Fernández says. In turn, the disrupted hydrogen-bond network lowers the entropic cost associated with forming protein-protein associations.