Improving AlphaFold 3 structural modeling by incorporating explicit crosslinks

Kosinski, J.

doi:10.1101/2024.12.03.626671

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bioRxiv · 10.1101/2024.12.03.626671

Improving AlphaFold 3 structural modeling by incorporating explicit crosslinks

Kosinski, J.

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Abstract

AlphaFold 3 has significantly advanced the modeling of macromolecular structures, including proteins, DNA, RNA, and their interactions with small molecules or post-translational modifications. However, challenges remain when modeling specific structural conformations or complexes with limited evolutionary data, such as protein-antibody complexes. Previous studies with AlphaFold2 demonstrated that adding distance restraints from crosslinking mass spectrometry (XL-MS) can improve predictions for such cases. In this study, we investigate whether XL-MS restraints can be incorporated into AlphaFold 3 by explicitly modeling crosslinks as covalently-bound ligands. Our results show that this approach is able to increase the accuracy of AlphaFold 3 models. We explore the opportunities and limitations of this method, which has been implemented as a proof-of-concept pipeline named AF3x, available at https://github.com/KosinskiLab/af3x.

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Kosinski, J.. 2024-12-03. Improving AlphaFold 3 structural modeling by incorporating explicit crosslinks. https://doi.org/10.1101/2024.12.03.626671

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