Fold or not to fold upon binding — does it really matter?

Protein interactions are usually determined by well-defined contact patterns. In this scenario, structuring of the interface is a prerequisite, which takes place prior or coupled to binding. Recent data, however, indicate plasticity of the templated folding pathway as well as considerable variations: polymorphism or dynamics in the bound-state. Conformational fluctuations in both cases are modulated by non-native, transient contacts, which complement suboptimal binding motifs to improve affinity. Here I discuss both templated folding and fuzzy binding mechanisms and propose a uniform scheme.