Conformation changes and the specificity of  protein-protein interaction

Joël Janin. Laboratoire d'Enzymologie et de Biochimie Structurales, CNRS, Gif-sur-Yvette, France.

Molecular docking algorithms assemble a two-pieces puzzle, which would be a child game if the components were rigid like a lock and a key. In reality, molecules (small or large) change conformation as they associate, a feature that all protein-protein docking procedures must take into account. Whereas existing procedures generally succeed when the conformation changes are small, they fail to reproduce large changes. These are nevertheless common, and in many biological systems, they are essential to the function. Changes seen upon association can be local (loop movement) or global (dimerization), and they may include disorder-to-order transitions, making protein-protein interaction of similar complexity to protein folding. 
Specific protein-protein complexes and homodimeric proteins form interfaces that are large and compact, with close-packed interface atoms. In contrast, the non-specific interaction observed in protein crystal packing generate small, loosely packed interfaces. These structural differences are easily interpreted in terms of geometric complementarity in cases where conformation changes are small and recognition takes place between preformed surfaces. In contrast, large changes at an interface imply that recognition first occurs between surfaces that are not complementary. A basic question in molecular assembly is how this process takes place, and whether we can reproduce it in docking procedure.