Protein-protein interactions mediate essentially all biological processes. A detailed understanding of these interactions is thus a major goal of modem biological chemistry. In recent years, genome sequencing efforts have revealed tens of thousands of novel genes, but the benefits of genome sequences will only be realized if these data can be translated to the level of protein function. While genome databases offer tremendous opportunities to expand our knowledge of protein -protein interactions, they also present formidable challenges to traditional protein chemistry methods. Indeed, it has become apparent that efficient analysis of proteins on a proteome-wide scale will require the use of rapid combinatoriol approaches. In this regard, phage display is an established combinatoriol technology that is likely to play on even greater role in the future of biology. This article reviews recent applications of phage display to the analysis of protein -protein interactions. With combinatorial mutagenesis strategies, it is now possible to rapidly map the binding energetics at protein -protein interfaces through statistical analysis of phage-displayed protein libraries. In addition, naive phage-displayed peptide libraries can be used to obtain small peptide ligands to essentially any protein of interest, and in many cases, these binding peptides act as antagonists or even agonists of natural protein functions. These methods ore accelerating the pace of research by enabling the study of complex protein -protein interactions with simple molecular biology methods. With further optimization and automation, it may soon be possible to study hundreds of different proteins in parallel with efforts comparable to those currently expended on the analysis of individual proteins.
