Molecular Glue-Augmented E2-Ubiquitin Recognition from A Computational Approach

Ubiquitin (Ub) is a small regulatory protein that tags unwanted or misfolded proteins for degradation by the proteasome. Molecular glues as small molecules stabilizing and augmenting protein-protein interactions have gained increasing attention in ubiquitination. Highly efficient computational approaches for the investigation of thermodynamics of molecular glue (MG)-Ub-protease systems remain absent. In this work, we introduced a cost-effective computational framework for all-atom characterization of the thermodynamics driving force in the cooperativity or molecule glue-induced enhancement of Ub-E2 recognition. Based on the testing bed involving the CDC34A-Ub protein-protein system and 18 unique molecule glues, we illustrate that our method could satisfactorily decoding the interaction thermodynamics inside the multimeric system. Specifically, our method enables both the ranking the protein-ligand MG-(E2-Ub) affinity and qualitatively capture the MG-induced E2-Ub interaction strengthening, which are generally unachievable with standard methods such as MM/GBSA and commonly applied scoring functions (e.g., AutoDock Vina). We additionally explore the general picture of the interfacial interactions in the multimeric complex, identifying important residues in the binding of molecular glue to Ub-E2 complex and also in Ub-E2 binding. Our computational approach could facilitate high-throughput virtual screening of potent molecular glues in assisting protein-protein recognition and ubiquitination.