PRosettaC outperforms AlphaFold3 for modeling PROTAC ternary complexes.

ABSTRACT: Targeted protein degradation via PROTACs offers a promising therapeutic strategy, yet accurate modeling of ternary complexes remains a critical challenge in degrader design. In this study, we systematically benchmark two leading structure prediction tools, AlphaFold-3 and PRosettaC, against a curated dataset of 36 crystallographically resolved ternary complexes. Using DockQ as a quantitative interface scoring metric, we assess the structural fidelity of predicted complexes under both scaffold-inclusive and stripped configurations. Our results demonstrate that AlphaFold-3's performance is often inflated by accessory proteins such as Elongin B/C or DDB1, which contribute to overall interface area but not degrader-specific binding. PRosettaC, on the other hand, leverages chemically defined an

SUBMITTER: Schulz JM 

PROVIDER: S-EPMC12568945 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature