Elastic Network Models and Molecular Dynamic Simulations Reveal the Molecular Basis of Allosteric Regulation in Ubiquitin-Specific Protease 7 (USP7)

Ubiquitin-specific protease 7 (USP7) is one of the most abundant deubiquitinases and plays an important role in various malignant tumors. However, the molecular mechanisms underlying USP7's structures, dynamics, and biological significance are yet to be investigated. In this study, we constructed the full-length models of USP7 in both the extended and compact state, and applied elastic network models (ENM), molecular dynamics (MD) simulations, perturbation response scanning (PRS) analysis, residue interaction networks as well as allosteric pocket prediction to investigate allosteric dynamics in USP7. Our analysis of intrinsic and conformational dynamics revealed that the structural transition between the two states is characterized by global clamp motions, during which the catalytic domain (CD) and UBL4-5 domain exhibit strong negative correlations. The PRS analysis, combined with the analysis of disease mutations and post-translational modifications (PTMs) further highlighted the allosteric potential of the two domains. The residue interaction network based on MD simulations captured an allosteric communication path which starts at CD domain and ends at UBL4-5 domain. Moreover, we identified a pocket at the TRAF-CD interface as a high-potential allosteric site for USP7. Overall, our studies not only provide molecular insights into the conformational changes of USP7, but also aid in the design of allosteric modulators that target USP7.