Structural Modeling of Protein Interactions by Analogy: Application to PSD-95

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Abstract
We describe comparative patch analysis for modeling the structures of multidomain proteins and protein complexes, and apply it to the PSD-95 protein. Comparative patch analysis is a hybrid of comparative modeling based on a template complex and protein docking, with a greater applicability than comparative modeling and a higher accuracy than docking. It relies on structurally defined interactions of each of the complex components, or their homologs, with any other protein, irrespective of its fold. For each component, its known binding modes with other proteins of any fold are collected and expanded by the known binding modes of its homologs. These modes are then used to restrain conventional molecular docking, resulting in a set of binary domain complexes that are subsequently ranked by geometric complementarity and a statistical potential. The method is evaluated by predicting 20 binary complexes of known structure. It is able to correctly identify the binding mode in 70% of the benchmark complexes compared with 30% for protein docking. We applied comparative patch analysis to model the complex of the third PSD-95, DLG, and ZO-1 (PDZ) domain and the SH3-GK domains in the PSD-95 protein, whose structure is unknown. In the first predicted configuration of the domains, PDZ interacts with SH3, leaving both the GMP-binding site of guanylate kinase (GK) and the C-terminus binding cleft of PDZ accessible, while in the second configuration PDZ interacts with GK, burying both binding sites. We suggest that the two alternate configurations correspond to the different functional forms of PSD-95 and provide a possible structural description for the experimentally observed cooperative folding transitions in PSD-95 and its homologs. More generally, we expect that comparative patch analysis will provide useful spatial restraints for the structural characterization of an increasing number of binary and higher-order protein complexes. Protein–protein interactions play a crucial role in many cellular processes. An important step towards a mechanistic description of these processes is a structural characterization of the proteins and their complexes. The authors developed a new approach to modeling the structure of protein complexes and multidomain proteins. The approach, called comparative patch analysis, complements the two currently existing approaches for structural modeling of protein complexes, comparative modeling, and protein docking. It limits the configurations refined by molecular docking to the structurally defined interactions of each of the complex components, or their homologs, with any other protein, irrespective of its fold; the final prediction corresponds to the best-scoring refined configuration. The authors applied comparative patch analysis to predict the structure of the core fragment of PSD-95, a five-domain protein that plays a major role in the postsynaptic density at neuronal synapses. The study suggests two alternate configurations of the core fragment that potentially correspond to the different functional forms of PSD-95. This finding provides a possible structural explanation for the experimentally observed cooperative folding transitions in PSD-95 and its homologs.