Frustration in protein complexes leads to interaction versatility

Disordered proteins can fold into a well-defined structure upon binding but these complexes are often fuzzy: the originally disordered partner adopts different binding modes when bound to different partners. Here we perform a systematic analysis of 160 proteins that form fuzzy complexes and demonstrate that the disordered partner displays a high degree of frustration in both the free and bound states. Although the folding of disordered regions upon binding reduces frustration relative to that of the unbound state, the interactions at the binding interface do not become fully optimized. In addition, we show that sub-optimal interactions lead to alternative frustration patterns in the complexes with different partners. These results demonstrate that disordered proteins do not always achieve fully optimal interactions in their complexes and their residual frustration leads to interaction versatility with different partners.