Computational analysis of energetic features and intermolecular interactions in protein-inhibitor USP7 complexes†

Abstract

Ubiquitin-specific proteases (USPs) play crucial roles in cellular processes and have emerged as promising therapeutic targets for various diseases, including cancer. This study utilizes a multi-faceted computational approach to investigate the binding mechanisms of small molecule inhibitors to USP7, a key member of the USP family. We combine transferable aspherical atom model (TAAM) calculations, density functional theory (DFT) analysis, and other computational tools to elucidate the electrostatic landscapes and non-covalent interactions in selected USP7-inhibitor complexes. Our findings demonstrate that electrostatic interactions are the dominant force in USP7-inhibitor binding, with charged residues contributing significantly to binding energies. Furthermore, the TAAM-based UBDB + EPMM method accurately captured the overall charge distribution, showing strong agreement with DFT calculations. We identified key residues involved in inhibitor binding, including previously overlooked contributors such as E298 and M407. The use of Hirshfeld surfaces and electrostatic potential (ESP) mapping provided detailed insights into the charge distribution and complementarity between USP7 and its inhibitors. Our results revealed that compounds with more concentrated positive charge distributions exhibited higher affinities Additionally, reduced density gradient (RDG) analysis offered further insight into the various non-covalent interactions at play. This study underscores the importance of long-range electrostatic interactions that extend beyond the immediate binding pocket. The insights gained from this work advance our understanding of USP7 inhibition and provide a valuable framework for the design of selective inhibitors targeting other members of the USP family.