SFB 1551 Seminar Series Event – Dr. Sergio Cruz-Leon

“Bridging cellular 3D imaging with physics-based simulations for biological discovery”

Dr. Sergio Cruz-Leon (MPI Biophysics, Frankfurt)

Summary:

Cellular function is governed by the structure, location, and dynamics of its densely packed molecular machines. Cryo-electron tomography (cryoET) captures 3D snapshots of intact cells at near molecular resolution. However, extracting reliable molecular identities and interactions from tomographic data remains challenging.

I will show how high-confidence 3D template matching (hcTM) for cryoET [1], coupled with multiscaling, enables us to model and simulate biological landscapes directly from cryoET data [1-3]. hcTM reliably localizes a wide range of macromolecular complexes in crowded cytoplasm and nuclei, producing spatial maps that are the basis to build simulation-ready models of subcellular environments.

Using this framework, we uncovered vault particles loaded with ribosomal cargo [1] and the unexpected ‘cracking’ of the nuclear pore complex (NPC) during HIV passage [2], and resolved the molecular architecture of human chromatin in situ [3]. We then applied it to an autophagy-related condensate directly in cells, demonstrating that a single amino-acid substitution strengthens intermolecular interactions, drives a liquid-to-glass mesoscale transition, and abolishes autophagic clearance. We thereby link a molecular alteration to changes in condensate material properties and biological function.

Integrating in situ imaging with multiscale simulation provides a pipeline for visual proteomics and sets the stage for simulating cellular processes in their native context.

Keywords: Visual proteomics, cryoET, high-confidence template matching, multi-scale simulations, HIV, chromatin, biomolecular condensates.

[1] Cruz-León, et al., Nat. Comm., 2024

[2] Kreysing*, Heidari*, Zila*, et al., Cell, 2025

[3] Kreysing*, Cruz-León*, Betz*, et al., BioRxiv, 2025