Abstract
Inhibitors of PDZ-peptide interactions have important implications in a variety of biological processes including treatment of cancer and Parkinson’s disease. Even though experimental studies have reported characterization of peptidomimetic inhibitors of PDZ-peptide interactions, the binding modes for most of them have not been characterized by structural studies. In this study we have attempted to understand the structural basis of the small molecule-PDZ interactions by in silico analysis of the binding modes and binding affinities of a set of 38 small molecules with known Ki or Kd values for PDZ2 and PDZ3 domains of PSD-95 protein. These two PDZ domains show differential selectivity for these compounds despite having a high degree of sequence similarity and almost identical peptide binding pockets. Optimum binding modes for these ligands for PDZ2 and PDZ3 domains were identified by using a novel combination of semi-flexible docking and explicit solvent molecular dynamics (MD) simulations. Analysis of the binding modes revealed most of the peptidomimectic ligands which had high Ki or Kd moved away from the peptide binding pocket, while ligands with high binding affinities remained in the peptide binding pocket. The differential specificities of the PDZ2 and PDZ3 domains primarily arise from differences in the conformation of the loop connecting βB and βC strands, because this loop interacts with the N-terminal chemical moieties of the ligands. We have also computed the MM/PBSA binding free energy values for these 38 compounds with both the PDZ domains from multiple 5 ns MD trajectories on each complex i.e. a total of 228 MD trajectories of 5 ns length each. Interestingly, computational binding free energies show good agreement with experimental binding free energies with a correlation coefficient of approximately 0.6. Thus our study demonstrates that combined use of docking and MD simulations can help in identification of potent inhibitors of PDZ-peptide complexes.
Highlights
Understanding the molecular basis of the interactions involving various PRMs (Peptide Recognition Modules) is crucial for deciphering protein interaction networks, and for potential therapeutic applications involving modulation of key interaction interfaces using small molecules
A set of 38 N-alkylated tetrapeptides belonging to one of these three groups were considered for detailed structural analysis of their binding modes as experimental binding affinities for these 38 peptidomimetics for PDZ2 as well as PDZ3 domains of PSD-95 protein were known
Binding modes for these inhibitors on PDZ2 and PDZ3 domains were identified by using a combination of docking and explicit solvent molecular dynamics (MD) simulations, which take into account complete flexibilities of the ligand as well as the receptor
Summary
Understanding the molecular basis of the interactions involving various PRMs (Peptide Recognition Modules) is crucial for deciphering protein interaction networks, and for potential therapeutic applications involving modulation of key interaction interfaces using small molecules. The transient nature of proteinprotein interactions mediated by PRMs and involvement of a small part of a polypeptide chain makes it amenable for disruption using small molecules. In this respect, small domains present in various proteins with different biological functions and recurrent in protein-protein interactions are the ones, which draw special attention. PDZ domain containing proteins are mostly involved in trafficking, recruiting and assembling of intracellular enzymes and membrane receptors into signaling transduction complexes. PDZ domains are known to increase the specificity and efficiency of intracellular interaction network of important PPIs downstream of receptor activation involving various signaling enzymes [4,5]
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