Structural and Dynamic Insights into Podocalyxin-Ezrin Inter- 2 action as a Target in Cancer Progression

<p dir="ltr">This repository accompanies the manuscript <b>“Structural and Dynamic Insights into Podocalyxin–Ezrin Interaction as a Target in Cancer Progression”</b> by <b>Mila Milutinovic, Stuart Lutimba, and Mohammed A. Mansour</b> (London South Bank University, 2025).</p><h4>The study applies an integrated computational workflow including protein–protein docking (HADDOCK 2.4), molecular dynamics (MD) simulations (OpenMM 8.1.2 and GROMACS 2024.2), and virtual screening (AutoDock 4.2.6) to characterize the PODXL–Ezrin interaction interface. </h4><h4><br><b>Key contributions include:</b></h4><ul><li><b>Structural Modeling</b>: Full-length AlphaFold-predicted models of PODXL (residues 322–558) and Ezrin, validated through stereochemical assessment (Ramachandran plots).</li><li><b>Mutation Analysis</b>: Examination of the clinically relevant PODXL R495W variant, revealing allosteric destabilization of Ezrin’s dormant state (e.g., increased F3–C-terminal distance from 2.59 Å to 3.40 Å).</li><li><b>Dynamic Characterization</b>: MD simulations (100 ns for WT and 20 ns for the mutant complex) indicate increased rigidity in the mutant, reflected by RMSD shifts (10.30 Å vs. 12.08 Å) and enhanced engagement of the pre-C-terminal loop.</li><li><b>Therapeutic Insights</b>: Virtual screening of an in-house library (>2,000 compounds) identifies <b>NSC305787</b> as a selective destabilizer of the R495W mutant (ΔG = −8.612 kcal/mol) via steric obstruction of PIP2 recruitment, while <b>THC</b> emerges as a stabilizer of the WT interface.</li></ul><p dir="ltr">Together, these findings support the PODXL–Ezrin complex as a viable and “druggable” target in PODXL-altered cancers (e.g., pancreatic cancer), with potential implications for inhibiting EMT and metastasis.</p>