Computational Binding Affinities of Disheveled PDZ Protein-Ligand Complexes

Wnt/ß-catenin signaling is critical for cell growth and development, with its hyperactive dysregulation implicated in the development of cancer. Current therapeutic research on inhibition of Wnt/ß-catenin signaling is impeded by the high cost of experimentally determining binding affinities. Consequently, interest has risen in screening potential inhibitors binding affinities with computational tools to reduce costs. Here, we test the validity of a computational molecular dynamics simulator, Binding Free Energy Estimator 2 (BFEE2), for determining peptide ligand affinity for Wnt/ß-catenin signaling. We focus on the Dishevelled (DVL) PDZ domain, a key mediator in WNT signaling through its ability to bind to various peptide ligands. We analyze the binding affinities of several DVL PDZ domain-peptide and domain-ligand complexes against previously established results to determine the validity of computational analysis. We conclude that computational molecular dynamics simulations were successful for peptide-ligand complexes with mixed results for small-molecule scenarios.