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PDZ-Peptide Interaction.


PDZ domains bind the disordered C-terminus of plasma membranes, mediating protein-protein interactions. These domains are highly promiscuous, and characterizing their binding specificity is critical to reveal their multiple roles in signal transduction. Crystallographic studies have revealed that binding PDZ scaffolds requires a four residue long strand anchored by a C-terminal hydrophobic residue. Based solely on the recognition motif of one co-crystal, we developed the first semi-flexible docking method to predict both the bound structure and affinity of disordered peptides with PDZ domains. A binding threshold of 10-5 M leads to sensitivity-specificity rates of 80%-80% in two independent datasets of 126 and 95 10-residue long natural and artificial peptides screened against the third PDZ domain of PSD95. Moreover, five peptides bound to 4 different PDZ domains are confirmed to form specific interactions, and their bound models are accurately predicted as the most stable complexes. The downhill pattern of the binding free energy landscapes reveals that disordered peptides undergo induced folding upon binding. Peptides with consensus C-terminal bind non-specifically, leading to the nucleation of a weak binding intermediate, which is followed by the zipping of the next residues into an extended network of contacts that delineate the specificity of the complex. This mechanism allows peptides to quickly probe PDZ domains, rapidly releasing those that do not attain enough affinity during binding. The kinetics of induced folding suggests that adapter proteins bind to disordered peptides to enhance the specificity of promiscuous interactions, while achieving association rates compatible with ordered proteins.


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