Affiliation:
1. *Department of Clinical Microbiology and Immunology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
2. †Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
Abstract
Abstract
Being able to accurately predict the three-dimensional structure of an Ab can facilitate Ab characterization and epitope prediction, with important diagnostic and clinical implications. In this study, we evaluated the ability of AlphaFold to predict the structures of 222 recently published, high-resolution Fab H and L chain structures of Abs from different species directed against different Ags. We show that although the overall Ab prediction quality is in line with the results of CASP14, regions such as the complementarity-determining regions (CDRs) of the H chain, which are prone to higher variation, are predicted less accurately. Moreover, we discovered that AlphaFold mispredicts the bending angles between the variable and constant domains. To evaluate the ability of AlphaFold to model Ab–Ag interactions based only on sequence, we used AlphaFold-Multimer in combination with ZDOCK to predict the structures of 26 known Ab–Ag complexes. ZDOCK, which was applied on bound components of both the Ab and the Ag, succeeded in assembling 11 complexes, whereas AlphaFold succeeded in predicting only 2 of 26 models, with significant deviations in the docking contacts predicted in the rest of the molecules. Within the 11 complexes that were successfully predicted by ZDOCK, 9 involved short-peptide Ags (18-mer or less), whereas only 2 were complexes of Ab with a full-length protein. Docking of modeled unbound Ab and Ag was unsuccessful. In summary, our study provides important information about the abilities and limitations of using AlphaFold to predict Ab–Ag interactions and suggests areas for possible improvement.
Funder
Israel Science Foundation
United States - Israel Binational Science Foundation
Publisher
The American Association of Immunologists
Subject
Immunology,Immunology and Allergy