Classification of protein complexes based on the biophysics of association

Based on measures of conformational change, interface area and hydrophobicity, we defined five types of protein‐protein complexes. Type I complexes have a “standard” interface area between 1400 Å 2 and 2000 Å 2 , and are formed, almost exclusively, by enzymes and their protein inhibitors that generally have a well‐packed interface with hydrophobic patches. Type II complexes have a large interface (ΔASA>2000 Å 2 ) and moderate conformational change upon association. This class is formed by protein pairs with very strong non‐transient functional coupling such as the RAS protein and its activating domain. Type III complexes have “standard” interface area, but less favorable desolvation free energy. Most antibody‐antigen pairs form such complexes. The next class, Type IV, contains the complexes with a small interface (<1400 Å 2 ). Complexes defined as Type V have as large or even larger interface than the Type II complexes (>2000 Å 2 ), but their component proteins are subject to substantial conformational change upon binding. This category mostly includes transient complexes involved in signal transduction, frequently with a cofactor regulating protein‐protein association. The results of CAPRI (Critical Assessment of Predicted Interactions), the first communitywide experiment devoted to protein docking, show that current methods are most successful when docking Type I and Type II complexes that are more stable and more hydrophobic than most other complexes of biological significance. The outcome of docking calculations is very uncertain for Type III complexes. Docking components of Type IV complexes generally yields poor results. Finally, Type V complexes are much more difficult to predict than others, and hence methods of measuring protein flexibility and predicting the magnitude of potential conformational changes are also of high interest.