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

ABSTRACT: 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 acros

SUBMITTER: Montisci F 

PROVIDER: S-EPMC12703653 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature