COMPASS: A Computational Pipeline to Identify Linkers Predicting Ubiquitinable PROTAC-Induced Ternary Complexes

PROteolysis TArgeting Chimeras (PROTACs) are bifunctional molecules designed to induce targeted protein degradation by forming a transient ternary complex between an E3 ubiquitin ligase and a protein of interest (POI), leading to the E3-mediated ubiquitination of the POI and its subsequent proteasomal degradation. Although PROTACs have emerged as highly promising therapeutic tools, rational design remains challenging due to limited structural understanding of the resulting assemblies, the dynamic nature of the ternary interface, and the critical role of the linker. Herein, we present COMPASS (COmputational Modeling of PROTAC Assembly with Structure-based Screening), a computational pipeline that allows the screening of linker libraries by assessing both ternary complex formation and ubiquitination potential. COMPASS functions as a high-sensitivity negative filter, identifying linkers that cannot form productive complexes and enabling their elimination before synthesis. Benchmarking against 20 crystallographic structures yielded <6 Å Cα-RMSD across all systems, outperforming existing methods. Retrospective validation across 8 distinct E3/POI systems (112 PROTACs) yielded 93% recall against degradation endpoints. Discriminative power is strongest when linker geometry is rate-limiting, a regime complementary to the stability and cooperativity effects that static structural modeling cannot capture.