Favorable scaffolds: proteins with different sequence, structure and function may associate in similar ways.

Proteins with similar structures may have different functions. Here, using a non-redundant two-chain protein-protein interface dataset containing 103 clusters, we show that this paradigm extends to interfaces. Whereas usually similar interfaces are obtained from globally similar chains, this is not always the case. Remarkably, in some interface clusters, although the interfaces are similar, the overall structures and functions of the chains are different. Hence, our work suggests that different folds may combinatorially assemble to yield similar local interface motifs. The preference of different folds to associate in similar ways illustrates that the paradigm is universal, whether for single chains in folding or for protein-protein association in binding. We analyze and compare the two types of clusters. Type I, with similar interfaces, similar global structures and similar functions, is better packed, less planar, has larger total and non-polar buried surface areas, better complementarity and more backbone-backbone hydrogen bonds than Type II (similar interfaces, different global structures and different functions). The dataset clusters may provide rich data for protein-protein recognition, cellular networks and drug design. In particular, they should be useful in addressing the difficult question of what the favorable ways for proteins to interact are.