Energetic Pathway Sampling in a Protein Interaction Domain

The affinity and specificity of protein-ligand interactions are influenced by energetic crosstalk within the protein domain. However, the molecular details of such intradomain allostery are still unclear. Here, we have experimentally detected and computationally predicted interaction pathways in the postsynaptic density 95/discs large/zonula occludens 1 (PDZ)-peptide ligand model system using wild-type and circularly permuted PDZ proteins. The circular permutant introduced small perturbations in the tertiary structure and a concomitant rewiring of allosteric pathways, allowing us to describe how subtle changes may reshape energetic signaling. The results were analyzed in the context of other members of the PDZ family, which were found to contain distinct interaction pathways for different peptide ligands. The data reveal a fascinating scenario whereby several energetic pathways are sampled within one single domain and distinct pathways are activated by specific protein ligands. [Display omitted] •PDZ domains contain energetic pathways that modulate specificity•Individual PDZ domains contain several distinct energetic pathways•Energetic pathways are activated by side chain residues in the protein ligand•The energetic pathway sampling is likely a general feature of protein domains Crosstalk within a protein influences the strength of its interactions. Hultqvist et al. identify the molecular wiring of such a crosstalk and reveal that several "communication channels" are sampled within the protein. Ligand binding activates a specific set of channels to modulate the selectivity.