From big molecules to smaller ones

Conclusions

Protein-protein interfaces are considerably larger than small molecule-protein interfaces. Nonetheless, mutational studies show only a small portion of the interface between hGH and its receptor is crucial for tight binding. This is likely a consequence of the fact that only a small number of contacts are necessary to generate high affinity. The interface is capable of adapting to mutational changes by reorganizing contact side chains. This plasticity affords the protein interface many options to adapt to mutational changes in its binding partner as they co-evolve.

It is possible to reduce protein binding domains by suitable preservation of the binding determinants and restructuring to stabilize the smaller scaffold. It is also possible to isolate peptides that bind to the same hot spot but have completely different structural motifs. Thus, there are many solutions to binding, but interestingly many seem to be directed to similar regions of the protein surface.

The use of molecular diversity methods coupled with structural insights is a powerful approach to redesigning binding peptides, and perhaps more importantly for discovering the rules that govern these interactions. Protein-protein targets have been generally intractable for identifying small molecule inhibitors by traditional pharmaceutical screening. Given the fact that small peptides can be isolated that block these interactions we may be on the verge of generating smaller molecular mimics for large protein signaling molecules.