preprint · ArXiv.org · 2025

Multiscale guidance of protein structure prediction with heterogeneous cryo-EM data

Rishwanth Raghu, Axel Levy, Gordon Wetzstein, Ellen D. Zhong

Cited by 1Open access

Abstract

Protein structure prediction models are now capable of generating accurate 3D structural hypotheses from sequence alone. However, they routinely fail to capture the conformational diversity of dynamic biomolecular complexes, often requiring heuristic MSA subsampling approaches for generating alternative states. In parallel, cryo-electron microscopy (cryo-EM) has emerged as a powerful tool for imaging near-native structural heterogeneity, but is challenged by arduous pipelines to transform raw experimental data into atomic models. Here, we bridge the gap between these modalities, combining cryo-EM density maps with the rich sequence and biophysical priors learned by protein structure prediction models. Our method, CryoBoltz, guides the sampling trajectory of a pretrained biomolecular structure prediction model using both global and local structural constraints derived from density maps, driving predictions towards conformational states consistent with the experimental data. We demonstrate that this flexible yet powerful inference-time approach allows us to build atomic models into heterogeneous cryo-EM maps across a variety of dynamic biomolecular systems including transporters and antibodies. Code is available at https://github.com/ml-struct-bio/cryoboltz .

Cite this paper

APA 7

Raghu, R., Levy, A., Wetzstein, G., & Zhong, E. D. (2025). Multiscale guidance of protein structure prediction with heterogeneous cryo-EM data. ArXiv.org. https://doi.org/10.48550/arxiv.2506.04490

MLA 9

Raghu, Rishwanth, et al. “Multiscale guidance of protein structure prediction with heterogeneous cryo-EM data.” ArXiv.org, 2025, https://doi.org/10.48550/arxiv.2506.04490.

Chicago

Raghu, Rishwanth, Axel Levy, Gordon Wetzstein, and Ellen D. Zhong. 2025. “Multiscale guidance of protein structure prediction with heterogeneous cryo-EM data.” ArXiv.org. https://doi.org/10.48550/arxiv.2506.04490.

Harvard

Raghu, R. et al. (2025) ‘Multiscale guidance of protein structure prediction with heterogeneous cryo-EM data’, ArXiv.org. Available at: https://doi.org/10.48550/arxiv.2506.04490.

BibTeX

@misc{raghu2025multiscale,
  title = {{Multiscale guidance of protein structure prediction with heterogeneous cryo-EM data}},
  author = {Raghu, Rishwanth and Levy, Axel and Wetzstein, Gordon and Zhong, Ellen D.},
  journal = {ArXiv.org},
  year = {2025},
  doi = {10.48550/arxiv.2506.04490}
}

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