ArticleBioinformatics advances2025
Challenges in predicting PROTAC-mediated protein-protein interfaces with AlphaFold reveal a general limitation on small interfaces.
Article in Bioinformatics advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Computational mapping of productive POI-E3 ligase conformations to guide de novo degrader design: application to WEE1 and PKMYT1 PROTACs.Journal of cheminformatics · 2026Article
- Metastable Protein-Protein Interactions as a Design Principle for PROTACs: Insights from the RIPK1-VHL System.JACS Au · 2026Article
- AlphaFold-driven discovery of oxysterol-binding protein-related protein-phosphoinositide 3-, 4-, and 5-phosphatase interactions using new generation confidence scores.Protein science : a publication of the Protein Society · 2026Article
- Article
- Prompt-based multimodal representation learning for drug repurposing.Briefings in bioinformatics · 2025Article
- Training bias and sequence alignments shape protein-peptide docking by AlphaFold and related methods.Protein science : a publication of the Protein Society · 2025Article
- Enhancing antibody-antigen interaction prediction with atomic flexibility.PLoS computational biology · 2025Article
- Assessment of Protein Complex Predictions in CASP16: Are we making progress?bioRxiv : the preprint server for biology · 2025Article
- AlphaFold3: An Overview of Applications and Performance Insights.International journal of molecular sciences · 2025Review
- MEGA PROTAC, MEGA DOCK-based PROTAC mediated ternary complex formation pipeline with sequential filtering and rank aggregation.Scientific reports · 2025Article
- An outlook on structural biology after AlphaFold: tools, limits and perspectives.FEBS open bio · 2025Review
- Standards for Computational Methods in Drug Design and Discovery: Simplified Guidance for Authors and Reviewers.Drug design, development and therapy · 2025Article
- Non-Markovian Dynamic Models Identify Non-Canonical KRAS-VHL Encounter Complex Conformations for Novel PROTAC Design.JACS Au · 2024Article
- Article
- Paralogue-selective degradation of the lysine acetyltransferase EP300.bioRxiv : the preprint server for biology · 2024Article
Corrections and comments
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Motivation: Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional molecules composed by ligands binding to a target protein and a E3-ligase complex, connected by a linker, that induce proximity-based target protein degradation. PROTACs are promising alternatives to conventional drugs against cancer. Predicting PROTAC-mediated complexes is often the first step for Results: Here, we investigate the potential causes of this limitation. We consider a set of 326 protein heterodimers orthogonal to the AF2 training set, and evaluate AF2 models focusing on the interface size and presence of interface ligand. Our results show that AF2-multimer predictions are sensitive to the size of the interface to predict even in the absence of ligands, with the majority of models being incorrect for the smallest interfaces. We also benchmark both AF2 and AF3 on a set of 28 PROTAC-mediated dimers and show that AF3 does not significantly improve upon the accuracy of AF2. The low accuracy of AF2 on complexes with small interfaces has strong implications for computational pipelines for PROTAC design, as these stabilize typically small interfaces, and more generally on any prediction task that involves small interfaces. Availability and implementation: All the models analyzed in this article are available in the Zenodo archive https://zenodo.org/records/14810843.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.