PRosettaC: Rosetta Based Modeling of PROTAC Mediated Ternary Complexes
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Abstract
Proteolysis-targeting chimeras (PROTACs), which induce degradation by recruitment of an E3 ligase to a target protein, are gaining much interest as a new pharmacological modality. However, designing PROTACs is challenging. Formation of a ternary complex between the protein target, the PROTAC, and the recruited E3 ligase is considered paramount for successful degradation. A structural model of this ternary complex could in principle inform rational PROTAC design. Unfortunately, only a handful of structures are available for such complexes, necessitating tools for their modeling. We developed a combined protocol for the modeling of a ternary complex induced by a given PROTAC. Our protocol alternates between sampling of the protein–protein interaction space and the PROTAC molecule conformational space. Application of this protocolPRosettaCto a benchmark of known PROTAC ternary complexes results in near-native predictions, with often atomic accuracy prediction of the protein chains, as well as the PROTAC binding moieties. It allowed the modeling of a CRBN/BTK complex that recapitulated experimental results for a series of PROTACs. PRosettaC generated models may be used to design PROTACs for new targets, as well as improve PROTACs for existing targets, potentially cutting down time and synthesis efforts. To enable wide access to this protocol, we have made it available through a web server (https://prosettac.weizmann.ac.il/).
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Computational modeling to predict ternary complex formation is a promising in silico approach for monovalent interactions.
“Another promising in silico approach involves computational modeling to predict ternary complex formation, adapting strategies currently employed for PROtAc design to monovalent interactions (Zaidman et al. 2020;weng et al. 2021).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Zaidman et al. 2020
The Results and Discussion report computational predictions of PROTAC-mediated ternary complexes and describe their potential for PROTAC design. The paper does not address adapting that approach to monovalent interactions, so it supports the modeling strategy but not the proposed application. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe computational pipeline PRosettaC starts by modeling POI-warhead and E3-recruitment ligand interactions, and then exploits PROTAC linker length constraints to drastically reduce the docking search space.
“Similarly, the computational pipeline PRosettaC starts by modeling POI-warhead and E3-recruitment ligand interactions, and then exploits the fact that PROTAC linkers have length constraints to drastically reduce the docking search space (Figure 5).71”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [71]
Zaidman et al. developed PRosettaC and performed retrospective PROTAC studies that delivered near-native ternary complexes.
“Similarly, Zaidman et al. developed the method PRosettaC and performed retrospective PRO-TAC studies that delivered near-native ternary complexes.176”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [176]
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- Authors
- Zaidman, D., Prilusky, J., & London, N.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- London, Nir
- Venue
- Journal of Chemical Information and Modeling
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-09-25
- Volume
- 60
- Issue
- 10
- Pages
- 4894-4903
- ISSN
- 1549-9596 (ISSN-L)
- 1549-960X
- PMC
- PMC7592117
- OpenAlex
- W3088870471
- Cited by
- 224
- References
- 57
- Citations by year
- 2026: 32 · 2025: 55 · 2024: 33 · 2023: 34 · 2022: 42 · 2021: 25 · 2020: 3
- FWCI
- 8.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Chemical Information and Modeling (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Israel Science Foundation (2462/19)
- Israel Cancer Research Fund
- Ministry of Culture and Sport (3-14763)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- PROTACs, protein-protein interaction, E3 ubiquitin ligase, cereblon, Bruton's tyrosine kinase, protein degradation, PROTAC design, Rosetta, web server, conformational sampling
- MeSH terms
- Ubiquitin-Protein Ligases, Proteolysis
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