Efficient Sampling of PROTAC-Induced Ternary Complexes

Abstract Proteolysis targeting chimeras (PROTACs) are bifunctional small molecules that recruit an E3 ligase to a target protein, leading to ubiquitin transfer and subsequent proteasomal degradation. The formation of ternary complexes is a crucial step in PROTAC-induced protein degradation, and gaining structural insights is essential for rational PROTAC design. In this study, we present a novel approach for efficiently sampling PROTAC-induced ternary complexes, which has been validated using 40 co-crystallized ternary complex structures. In comparison to protein-protein docking-based integrative approaches, our method achieved an impressive success rate of 97% and 50% retrospectively, measured by C α -RMSD to the crystal structure within 10 and 4 Å, respectively, with an average CPU time of 4 hours. Notably, utilizing unbound protein structures, the C α -RMSD values between the predicted and experimental structures were consistently within 7 Å across six WDR5-PROTAC-VHL ternary structures. Our open-source software enables the modeling of ternary structures in a single step and holds promise for enhancing PROTAC design efforts. TOC