Design sequence

EGFR

A cancer target with six approved drugs, where the side effect that caps the dose comes from hitting the target itself and shows up in the skin. An earlier design of ours bound it at 630 pM.

01 · Proteome

Signal spreads across a map of how human proteins interact.All natural human proteins

A six-part sequence built from real computational objects. It begins with Synthyra’s predicted human protein-interaction map of 19,982 reviewed proteins, in which a signal propagates along predicted edges. The map resolves to a single protein, EGFR (UniProt P00533, node 3,078), whose experimentally determined domain III from PDB entry 1YY9 is shown as a space-filling molecular surface moving along its elastic-network normal modes, with the cetuximab variable fragment in its crystallographic pose. The sequence then adds a SwissBioPics human-cell diagram carrying the same network placed by curated UniProt subcellular-location annotation, a rail of six approved EGFR-family inhibitors linked to the proteins they are predicted to bind, and Human-GEM version 2.0.0, a published genome-scale metabolic model of 12,931 reactions and 8,461 metabolites, drawn as a metabolite-by-reaction incidence map. One candidate column and nine constraint rows are added while the published model is held fixed. A single candidate binder is then refined across four design passes, jointly constrained by the interaction map and the metabolic model, while the readouts update.

Info

Where every object on screen came from.

Interaction map: Synthyra Atlas-PPI predicted human interactome, 19,982 reviewed proteins.
Cell diagram: SwissBioPics animal cell, SIB Swiss Institute of Bioinformatics, CC BY 4.0. Redrawn as line art.
Protein structure: PDB 1YY9 chain A, residues 310 to 514: EGFR domain III, the cetuximab epitope. Public domain (CC0). Li et al., Cancer Cell, 2005.
Motion: Anisotropic network model normal modes over C-alpha atoms within 13 angstrom, first six non-trivial modes.
Metabolic model: Human-GEM v2.0.0, SysBioChalmers, CC BY 4.0. Ten central-metabolism subsystems shown, currency metabolites hidden.
Approved inhibitors: Gefitinib, osimertinib, afatinib, dacomitinib, lapatinib and neratinib, from the Atlas protein-ligand screen. Dacomitinib is now authorised in the EU only.
Ontology terms: EGF receptor binding (GO:0005154, 19 proteins), epidermis development (GO:0008544, 26), cornified envelope (GO:0001533, 37).
Pathway and disease identifiers: Reactome R-HSA-177929, Signaling by EGFR. MONDO:0005233, non-small cell lung carcinoma, is the modeling context.
Measured result: Design dsm_egfr_10 bound recombinant EGFR at 630 pM in its best replicate, against a 1.20 nM literature reference. The stage shows cetuximab.

Nothing in this sequence is an illustration. Every readout is a prediction, and it shows direction rather than an absolute number. What each object is and where it came from are in the disclosure above.