Journal ArticlePredicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometryDixon, Tom; MacPherson, Derek; Mostofian, Barmak; Dauzhenka, Taras; Lotz, Samuel; McGee, Dwight; Shechter, Sharon; Shrestha, Utsab R.; Wiewiora, Rafal; McDargh, Zachary A.; Pei, Fen; Pal, Rajat; Ribeiro, João V.; Wilkerson, Tanner; Sachdeva, Vipin; Gao, Ning; Jain, Shourya; Sparks, Samuel; Li, Yunxing; Vinitsky, Alexander; Zhang, Xin; Razavi, Asghar M.; Kolossváry, István; Imbriglio, Jason; Evdokimov, Artem; Bergeron, Louise; Zhou, Wenchang; Adhikari, Jagat; Ruprecht, Benjamin; Dickson, Alex; Xu, Huafeng; Sherman, Woody; Izaguirre, Jesus A.Abstract Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated in diseases. A key step in this process is the formation of a ternary complex where a heterobifunctional molecule induces proximity of an E3 ligase to a protein of interest (POI), thus facilitating ubiquitin transfer to the POI. In this work, we characterize 3 steps in the TPD process. (1) We simulate the ternary complex formation of SMARCA2 bromodomain and VHL E3 ligase by combining hydrogen-deuterium exchange mass spectrometry with weighted ensemble molecular dynamics (MD). (2) We characterize the conformational heterogeneity of the ternary complex using Hamiltonian replica exchange simulations and small-angle X-ray scattering. (3) We assess the ubiquitination of the POI in the context of the full Cullin-RING Ligase, confirming experimental ubiquitinomics results. Differences in degradation efficiency can be explained by the proximity of lysine residues on the POI relative to ubiquitin.2022-12-0110370111Nature Communications1312041-1723https://doi.org/10.1038/s41467-022-33575-41761320National Science Foundation