Frustration in Fuzzy Protein Complexes Leads to Interaction Versatility

Disordered
proteins frequently serve as interaction hubs involving
a constrained variety of partners. Complexes with different partners
frequently exhibit distinct binding modes, involving regions that
remain disordered in the bound state. While the conformational properties
of disordered proteins are well-characterized in their free states,
less is known about the molecular mechanisms by which specificity
can be achieved not with one but with multiple partners. Using the
energy landscape theory concept of protein frustration, we demonstrate
that complexes of disordered proteins exhibit a high degree of local
frustration, especically at the binding interface. These suboptimal
interactions lead to the possibility of multiple bound substates,
each displaying distinct frustration patterns, which are differently
populated in complexes with different partners. These results explain
how specificity of disordered proteins can be achieved without a single
common bound conformation and how the confliict between different
interactions can be used to control the binding to multiple partners.