Identification of specificity and promiscuity of PDZ domain interactions through their dynamic behavior.

PDZ domains (PDZs), the most common interaction domain proteins, play critical roles in many cellular processes. PDZs perform their job by binding specific protein partners. However, they are very promiscuous, binding to more than one protein, yet selective at the same time. We examined the binding related dynamics of various PDZs to have insight about their specificity and promiscuity. We used full atomic normal mode analysis and a modified coarse-grained elastic network model to compute the binding related dynamics. In the latter model, we introduced specificity for each single parameter constant and included the solvation effect implicitly. The modified model, referred to as specific-Gaussian Network Model (s-GNM), highlights some interesting differences in the conformational changes of PDZs upon binding to Class I or Class II type peptides. By clustering the residue fluctuation profiles of PDZs, we have shown: (i) binding selectivities can be discriminated from their dynamics, and (ii) the dynamics of different structural regions play critical roles for Class I and Class II specificity. s-GNM is further tested on a dual-specific PDZ which showed only Class I specificity when a point mutation exists on the betaA-betaB loop. We observe that the binding dynamics change consistently in the mutated and wild type structures. In addition, we found that the binding induced fluctuation profiles can be used to discriminate the binding selectivity of homolog structures. These results indicate that s-GNM can be a powerful method to study the changes in binding selectivities for mutant or homolog PDZs.