Structural biology (cryo-EM CRO)

Cryo-electron microscopy (cryo-EM) has turned macromolecular structure determination into a B2B contract-research pipeline for structure-based drug design (SBDD). It vitrifies proteins in a thin film of amorphous ice and reconstructs an atomic 3D map from thousands of low-dose 2D projection images, bypassing the years of failed crystallization that X-ray crystallography demanded for membrane proteins such as GPCRs and ion channels. Drug developers now receive drug-design-grade target maps in weeks. The stack runs from vitrification (Thermo Scientific Vitrobot) through 300 kV cryo-TEM (Titan Krios G4) and direct-electron detectors (Falcon 4i / Gatan K3) to computational reconstruction (RELION, cryoSPARC) and atomic model building (Phenix, Coot), delivered as PDB-validated coordinates. Structures feed filings regulated by the FDA, EMA and NMPA, with resolution validated against the Fourier-shell correlation (FSC) 0.143 gold standard and deposited under wwPDB rules. The six organizations in this projection span the hardware backbone (Thermo Fisher, Gatan) and the CRO layer (NanoImaging Services, WuXi AppTec, Proteros, Gandeeva).

Key directions of cryo-EM structural biology as a service:

1. Displacing X-ray crystallography: atomic structures of recalcitrant membrane proteins without crystallization.
2. Drug-design resolution: direct-electron detectors and refinement push maps to roughly 2-3 A, sufficient for rational inhibitor design.
3. Cryo-EM plus machine learning: integration of experimental structures with ML binding prediction for hit finding.
4. Fragment and screening services: cryo-EM coupled to compound-library and fragment screening as a single CRO offering.

Sectoral value chain#

[sample prep] ──> [vitrification] ──> [grid screening] ──> [data collection]
                                                          │
                                                (atomic reconstruction)
                                                          │
                                                          ▼
[PDB-validated delivery] <─── [model building] <─────┘

Value chain levels#

Cross-cutting technologies of the sector:

• cryo-em: single-particle cryo-EM at 300 kV (Titan Krios) with direct-electron detection.
• x-ray-crystallography: complementary synchrotron crystallography (e.g. ESRF beamlines).
• structure-prediction: AlphaFold models integrated with experimental cryo-EM maps.

The stack spans vitrification physics, direct electron detection and computational reconstruction.

1. Vitrification and 300 kV cryo-TEM:
   • a Vitrobot plunges the grid into liquid ethane at about -160 C, cooling the film fast enough (hundreds of thousands of degrees per second) to freeze water as amorphous ice rather than destructive crystals.
   • the Titan Krios G4 images the grid at 300 kV with a Cold-FEG source, SelectrisX energy filter and Falcon 4i detector, running EPU automated acquisition across 12 autoloader grids.
2. Direct-electron detection and reconstruction:
   • direct detectors (Gatan K3, Falcon 4i) count individual electrons at high frame rates, enabling movie-based motion correction; cryoSPARC and RELION then perform CTF estimation, CNN-based particle picking, 2D classification and 3D refinement to roughly 2-3 A.
3. Model building and PDB validation:
   • Phenix and Coot fit the amino-acid sequence into the density map, and resolution is validated by the FSC 0.143 criterion before wwPDB deposition and B2B coordinate delivery.