Zhao, H.; Schiesser, S.; Tyrchan, C.; Czechtizky, W.

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-RMSD to the crystal structure within 10 and 4 &Aring, respectively, with an average CPU time of 4 hours. Notably, utilizing unbound protein structures, the C-RMSD values between the predicted and experimental structures were consistently within 7 &Aring 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.