{"title":"Challenging cases for AlphaFold: two multidomain proteins with zinc-binding-, phosphorylation- or dimerization-driven conformational changes","authors":"Yinshan Yang, Hélène Déméné","doi":"10.1007/s00249-026-01854-3","DOIUrl":null,"url":null,"abstract":"<div><p>Advances in artificial intelligence, particularly in deep learning, are transforming the field of protein structure prediction. AlphaFold has emerged as a benchmark tool due to its remarkable ability to model protein folding based solely on amino acid sequences. Nevertheless, despite these impressive achievements, several prediction failures still occur. In this study, we focus on two multidomain proteins, LicT from <i>Bacillus subtilis</i> and P1 from the Rice Yellow Mottle Virus, that have long resisted structural characterization. Both proteins exhibit inter-domain flexibility, dimerization, and dynamic behavior in response to phosphorylation (for LicT) or zinc binding (for P1). Here, we screen the performances of AlphaFold versions against these two proteins endowed with a complex conformational landscape and show the present impossibility to correctly predict all domains simultaneously.</p></div>","PeriodicalId":548,"journal":{"name":"European Biophysics Journal","volume":"55 4","pages":"747 - 756"},"PeriodicalIF":2.3000,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Biophysics Journal","FirstCategoryId":"2","ListUrlMain":"https://link.springer.com/article/10.1007/s00249-026-01854-3","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOPHYSICS","Score":null,"Total":0}
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Abstract
Advances in artificial intelligence, particularly in deep learning, are transforming the field of protein structure prediction. AlphaFold has emerged as a benchmark tool due to its remarkable ability to model protein folding based solely on amino acid sequences. Nevertheless, despite these impressive achievements, several prediction failures still occur. In this study, we focus on two multidomain proteins, LicT from Bacillus subtilis and P1 from the Rice Yellow Mottle Virus, that have long resisted structural characterization. Both proteins exhibit inter-domain flexibility, dimerization, and dynamic behavior in response to phosphorylation (for LicT) or zinc binding (for P1). Here, we screen the performances of AlphaFold versions against these two proteins endowed with a complex conformational landscape and show the present impossibility to correctly predict all domains simultaneously.
期刊介绍：
The journal publishes papers in the field of biophysics, which is defined as the study of biological phenomena by using physical methods and concepts. Original papers, reviews and Biophysics letters are published. The primary goal of this journal is to advance the understanding of biological structure and function by application of the principles of physical science, and by presenting the work in a biophysical context.
Papers employing a distinctively biophysical approach at all levels of biological organisation will be considered, as will both experimental and theoretical studies. The criteria for acceptance are scientific content, originality and relevance to biological systems of current interest and importance.
Principal areas of interest include:
- Structure and dynamics of biological macromolecules
- Membrane biophysics and ion channels
- Cell biophysics and organisation
- Macromolecular assemblies
- Biophysical methods and instrumentation
- Advanced microscopics
- System dynamics.
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