Poster Presentation: "Structural and Dynamic Basis of Phosphorylation-Mediated HSP90 Conformational Switching Controls Epichaperome Assembly and Cellular Proliferation" at The 2nd NextGen Conversation in Biomolecular Structure and Dynamics.

Cancer cells adapt to fluctuating microenvironments by rewiring intracellular signaling and protein–protein interaction networks, including through stress-induced epichaperome assemblies that support malignant phenotypes and tumor-associated cells. However, the structural basis of epichaperome formation remains unclear. In this study, we apply a computational systems biology approach, using molecular modeling and dynamics simulations, to define how post-translational modifications (phosphorylation) drive epichaperome assembly of a pentameric  complex (HSP90β(A-B)–HSP70(2)–HOP) by comparing WT (HSP90S226/S255), phosphomimetic (S226E/S255E), and non-phosphorylatable (S226A/S255A) variants. The simulations show that phosphorylation of the HSP90 charged linker promotes β-strand formation and stabilizes inter-protomer contacts, enabling higher-order multimerization consistent with epichaperome structures observed in tumor cells. These results provide a mechanistic framework for how tumors hijack chaperone networks to modulate immune pathways and suggest new strategies to disrupt pathogenic PPI networks and restore anti-tumor immunity.