Structure-informed theoretical modeling defines principles governing avidity in bivalent protein interactions

In signaling cascades, where domain-motif interactions tend to interact with relatively low affinity (allowing for reversibility), signaling proteins often encode multiple domains or motifs. This presents the possibility for avidity where multivalent binding drastically increases the interaction strength and duration. However, given the large combinatorial space, predicting and validating multivalent interactions that interact with avidity is a challenge. Here, we integrate mechanistic modeling, structure-based analysis, and experimental approaches as a framework for defining the conditions under which avidity plays a role. We explore the tandem SH2 domain family of interactions with bisphos