Design sequence

Acetylcholinesterase

The Alzheimer’s target where thirty years of chemistry produced excellent binders, four approved drugs, and no change to the course of the disease.

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, acetylcholinesterase (UniProt P22303, node 4,801), whose experimentally determined catalytic subunit from PDB entry 1B41 is shown as a space-filling molecular surface moving along its elastic-network normal modes, with the snake-venom inhibitor fasciculin-II 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 cholinesterase inhibitors that reached US approval, 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. All readouts are modeled and relative.

Sources and licenses

Every object below is a real computational artifact. Readouts are modeled.

Interaction map: Synthyra Atlas-PPI predicted human interactome, 19,982 reviewed proteins. Edges are model predictions.
Cell diagram: SwissBioPics animal cell, SIB Swiss Institute of Bioinformatics, CC BY 4.0. Redrawn as single-weight line art.
Protein structure: PDB 1B41 chain A, residues 5 to 543: the catalytic subunit of human acetylcholinesterase. Public domain (CC0). Kryger et al., Acta Crystallogr D, 2000.
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, rows and columns reordered. No reaction added or removed.
Approved inhibitors: Donepezil, rivastigmine, galantamine, tacrine, ambenonium and edrophonium, from the Atlas protein-ligand screen. The first four were approved for dementia, the last two for other cholinergic indications.
Ontology terms: Acetylcholine binding (GO:0042166, 10 proteins), acetylcholine receptor signaling pathway (GO:0095500, 25 of 26 in this map), neuromuscular junction (GO:0031594, 5).
Pathway and disease identifiers: Reactome R-HSA-112311, Neurotransmitter clearance. MONDO:0004975, Alzheimer disease, is the modeling context.

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.