Signaling pathways of PDZ2 domain: a molecular dynamics interaction correlation analysis

PDZ domains are found in many signaling proteins. One of their functions is to provide scaffolds for forming membrane-​assocd. protein complexes by binding to the carboxyl termini of their partners. PDZ domains are thought also to play a signal transduction role by propagating the information that binding has occurred to remote sites. In this study, a mol. dynamics (MD) simulation-​based approach, referred to as an interaction correlation anal., is applied to the PDZ2 domain to identify the possible signal transduction pathways. A residue correlation matrix is constructed from the interaction energy correlations between all residue pairs obtained from the MD simulations. Two continuous interaction pathways, starting at the ligand binding pocket, are identified by a hierarchical clustering anal. of the residue correlation matrix. One pathway is mainly localized at the N-​terminal side of helix α1 and the adjacent C-​terminus of loop β1-​β2. The other pathway is perpendicular to the central β-​sheet and extends toward the side of PDZ2 domain opposite to the ligand binding pocket. The results complement previous studies based on multiple sequence anal., NMR, and MD simulations. Importantly, they reveal the energetic origin of the long-​range coupling. The PDZ2 results, as well as the earlier rhodopsin anal., show that the interaction correlation anal. is a robust approach for detg. pathways of intramol. signal transduction.