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

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

Keywords: Computational Biology and Bioinformatics, Generative Models

TL;DR: We propose a diffusion guidance approach for fitting atomic models into experimental density maps using pretrained protein structure prediction models.

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.

Primary Area: Machine learning for sciences (e.g. climate, health, life sciences, physics, social sciences)

Submission Number: 18704