Linker-Driven Sampling of PROTAC-Induced Ternary Complexes

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that recruit an E3 ligase to a protein of interest, thereby promoting ubiquitin transfer and subsequent proteasomal degradation. Formation of the ternary complex is a key step in PROTAC-induced degradation, and structural insight into these complexes is important for rational PROTAC design. Here, we present a computational approach for sampling PROTAC-induced ternary complexes by reducing the search space to the conformational degrees of freedom of the linker. Evaluated on 40 cocrystal ternary complex structures, the method achieved retrospective success rates of 97% and 50% at Cα-RMSD thresholds of 10 and 4 Å from the crystal structures, respectively. Using unbound protein structures as input, the predicted ternary complexes remained within 7 Å of the experimental structures across six WDR5-PROTAC-VHL complexes. Our open-source software, TERNIFY, enables ternary-complex modeling in a standalone workflow without separate protein-protein docking and linker-sampling steps.