Before these unexpected results, most researchers in our field would have predicted that entropys contribution to protein-protein interactions would be zero or negligible, says Wand. But now its clearly an important component of the total energy in protein binding.
Because of this new information, the researchers suggest that the entropy component may explain why drug design fails more often than it works. Currently, drugs are designed generally based on the precise structures of their biological targets, active regions on proteins that are intended to inhibit key molecules. However, the number of designed molecules actually binding to their targets is low for many engineered molecules. We think that this is because the design is based on a model of a static protein, not the moving, hyper protein that is constantly changing shape, say Wand. We need to figure out how this new information fits in and perhaps drug design could be significantly improved.
Future directions include understanding whether the principles revealed by this study are universal and impact the thousands of protein-protein interactions that underlie biology and disease. As Wand explains, Protein-protein interactions are central to signalling, which is often the molecular origin of diseases. Cancer, diabetes, and asthma are three important examples. We are currently looking at the role of protein entropy in the control of criti
Contact: Karen Kreeger
University of Pennsylvania School of Medicine