Insights into the Structural and Energetic Descriptions of Ubiquitin Specific Protease 7 (USP7) Catalytic Mechanisms by Hybrid QM/MM Simulations.

We have reported the first computational study about USP7 reaction mechanism with the substrate Ubiquitin-Rhodamine 110-G (Ub-Rho) using a robust methodology that integrated homology modeling, classical molecular dynamics (MD) simulations, protein-protein interaction fingerprints (IFPs) analysis, principal components analysis (PCA) and clustering, and the hybrid QM/MM simulations using the adaptive string method (ASM). The results presented in this work could be useful to understand the dynamic nature of USP7 enzyme-substrate complexes. In this sense, we have provided a detailed structural description of the most relevant conformational changes observed in our simulations, which could be used as reference for modeling more complicated USP7's enzyme-substrate complexes. On the other hand, our descriptions of the protein-protein interactions of Ub-Rho's residues at P5 to P1' positions with the CD's active site, and the geometries of the stationary states located along the MFEP could be considered for designing new potent and selective inhibitors for USP7's activity.