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Bridging prediction and reality: Comprehensive analysis of experimental and AlphaFold 2 full-length nuclear receptor structures
Open accessPublished version of a preprint
Abstract
AlphaFold 2 has revolutionized protein structure prediction, yet systematic evaluations of its performance against experimental structures for specific protein families remain limited. Here we present the first comprehensive analysis comparing AlphaFold 2-predicted and experimental nuclear receptor structures, examining root-mean-square deviations, secondary structure elements, domain organization, and ligand-binding pocket geometry. While AlphaFold2 achieves high accuracy in predicting stable conformations with proper stereochemistry, it shows limitations in capturing the full spectrum of biologically relevant states, particularly in flexible regions and ligand-binding pockets. Statistical analysis reveals significant domain-specific variations, with ligand-binding domains showing higher structural variability (CV = 29.3%) compared to DNA-binding domains (CV = 17.7%). Notably, Alphafold 2 systematically underestimates ligand-binding pocket volumes and captures only single conformational states in homodimeric receptors where experimental structures show functionally important asymmetry. These findings provide critical insights for structure-based drug design targeting nuclear receptors and establish a framework for evaluating Alphafold 2 predictions across other protein families.
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Metadata
- Authors
- Mazhibiyeva, A., Pham, T. T., Pats, K., Lukac, M., & Molnár, F.
- Affiliations
- Nazarbayev University (KZ)
- ITMO University (RU)
- Department of Computer Networks and Engineering, Hiroshima City University, 3-4-1 Oozukahigashi, Asaminami-ku, Hiroshima-shi, 731–3166, Japan
- Corresponding author
- Molnár, Ferdinand
- Venue
- Computational and Structural Biotechnology Journal
- Published
- 2025-01-01
- Volume
- 27
- Pages
- 1998-2013
- ISSN
- 2001-0370 (ISSN-L)
- PMC
- PMC12149446
- OpenAlex
- W4410398694
- Cited by
- 13
- References
- 11
- Citations by year
- 2026: 8 · 2025: 5
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Computational and Structural Biotechnology Journal (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Nazarbayev University Repository (Nazarbayev University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Nazarbayev University (091019CRP2108)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- AlphaFold2, nuclear receptors, protein structure prediction, forecast evaluation, binding pocket, DNA-binding domain, conformational heterogeneity, structure-based drug design, full-length protein structure
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