DOI: 10.1038/s41467-025-56572-9
Key Points:
- Introduces AlphaFold-Metainference, a new method combining AlphaFold predictions with physics simulations
- Notable because AlphaFold was trained on structured proteins but shows surprising accuracy with disordered ones
- Validated against experimental data from 11 different disordered proteins using SAXS (small-angle X-ray scattering)
- Further validated against detailed simulations of two neurodegenerative disease-related proteins (Abeta and alpha-synuclein)
Major Implications:
- Could revolutionize study of disordered proteins involved in diseases like Alzheimer's and Parkinson's
- Suggests AlphaFold may be detecting fundamental principles of protein behavior beyond just structured proteins
- Opens new possibilities for drug discovery and personalized medicine
- May require rethinking our definition of protein "disorder"
Technical Details:
- AlphaFold provides distance predictions between amino acids
- Limited to predictions up to ~22 angstroms
- Metainference uses physics simulations to explore possible conformations within AlphaFold's predictions
Limitations Discussed:
- 22 angstrom distance prediction limit means some longer-range interactions may be missed
- Particularly relevant for very extended disordered regions
- May need integration with other experimental techniques for complete picture
