Data-Driven Generation of Conformational Ensembles and Ternary Complexes for PROTAC and Other Chimera Systems

We present the protolysis-targeting chimera (PROTAC) Conformer Generator, a fast and knowledge-based tool for generating robust conformational ensembles of PROTACs and other chimeric degraders. The modeling protocol integrates conformer generation, rigid-body ternary complex (TC) assembly, and conformational sampling strategies that address the inherent flexibility and complexity of these molecules. Each modeled TC is evaluated using a clash-score and a surface-score, designed to prioritize sterically and geometrically plausible models with favorable protein surface interactions. The protocol was validated using experimentally determined PROTAC-mediated TC structures from the Protein Data Bank and "PROTAC-like" structures from the Cambridge Structural Database, demonstrating accuracy across diverse systems. The results show that the PROTAC Conformer Generator can reliably reproduce experimental conformations and generate simple TC models that recapitulate the relative orientations between E3 ubiquitin ligase and the protein of interest as observed in protein crystal structures. This robust validation supports the method's reliability and establishes a reference framework for degrader modeling studies. The PROTAC Conformer Generator provides a structured and validated workflow for modeling and assessing degrader conformations and ternary complexes, enabling rapid ensemble generation and downstream integration into relevant early stage drug design pipelines.