MODEL PROTEIN FOLDING · BIOLOGY · THERMODYNAMIC HYPOTHESIS · under KEEPER ERIS

Anfinsen’s Dogma · The Sequence Knows

Anfinsen unfolded ribonuclease A, scrambled its 4 disulfides, and watched it refold to full activity. The native fold is the free-energy minimum, written in the sequence. Random pairing of 8 cysteines gives 105 options, and only 1 is native.

Dave (t249u): "can you build some pages on protein folding, the math and the difficulty, edutaiton please, use this wasm engine"

Dave’s I-13 engine on this page

booting I-13 v0.3…

LIT What the VM computes here: The VM counts the possible disulfide pairings recursively, as the double factorial (2n−1)!!, and computes the Boltzmann equilibrium constant e^(ΔG/RT) with its own exp series.

LIT Christian Anfinsen’s ribonuclease A experiments (Nobel Prize in Chemistry 1972; Science 181:223, 1973): the enzyme (124 residues, 8 cysteines, 4 disulfides) was reduced and unfolded in 8 M urea with β-mercaptoethanol. When the denaturant was removed slowly, it refolded and regained nearly full activity.

LIT If it was reoxidised while still in urea, the disulfides formed at random (“scrambled” RNase) with about 1% activity. Eight cysteines can pair in 7 × 5 × 3 × 1 = 105 ways, and 1/105 ≈ 0.95%. Traces of β-mercaptoethanol let the scrambled protein shuffle back to the native pairs Cys26–84, 40–95, 58–110 and 65–72.

LIT Thermodynamic hypothesis: the native structure is the one with the lowest Gibbs free energy, determined by the amino-acid sequence in its normal environment.

AMBER Exceptions that refine the dogma: chaperones (GroEL/ES) prevent aggregation but don’t encode the fold; some proteins are kinetically trapped or metastable (serpins); prions have a second stable fold; intrinsically disordered proteins have no single fold.

WALL The dogma says the answer is in the sequence. It does not say how to read it, which is the prediction problem on the AlphaFold page.

Lab MODEL interactive, computed on the I-13 VM

cysteines · stability ΔG kcal/mol

Sources (browsed Oct 2026)

  1. Anfinsen Nobel lecture (1972), Studies on the principles that govern the folding of protein chains
  2. Anfinsen (1973) Principles that govern the folding of protein chains, Science 181:223
  3. Klink et al. (2000) disulfide bonds of RNase A (Cys26–84, 40–95, 58–110, 65–72), Eur J Biochem

MODEL Two agents, as Dave set for every world. The ARTIST folds the 24-residue HP chain S2 HHPPHPPHPPHPPHPPHPPHPPHH on the cubic (3D) lattice with pivot, corner and kink moves. The CRITIC judges each move (Metropolis at temperature T) and scores the best fold as −E/13 (E_ref = -13, best found by our annealing; literature optimum −13). It also has Dave’s I-13 VM recount every kept fold from raw coordinates. Rendered with Three.js r160 from a pinned CDN, devicePixelRatio capped at 2. Drag to orbit, scroll to zoom.

LIT on load: the seal is recomputed, the page’s facts are re-checked as arithmetic (throws on mismatch), 200 seeded ARTIST rounds must improve, the workspace loop logs 5 entries, and the OBJ and SVG exports must agree. Then the engine boots, its SHA-256 is checked, and the page’s VM results are compared with independent JS.

Gallery of kept folds (WebGL snapshots):

Workspace improvement loop: instructions for agents MODEL

  1. Measure: every 40 rounds, record the acceptance rate, the best score, the best E and the rounds since the last improvement.
  2. Try next: after a 40-round plateau, reheat T ×1.5. If acceptance is under 15%, warm T ×1.25; if over 45%, cool T ×0.7; otherwise anneal T ×0.9.
  3. Log back: append {entry, round, measured, tried, T} to the workspace log (in the JSON export and the list below), and have the I-13 VM recount the best fold.
  4. Repeat, forever: never stop improving. Re-check every claim against the engine and the sources before you make it.

Live workspace log:

    Shared board MODEL ARTIST ↔ CRITIC

      Background art: AMBER MODEL a generative field seeded from this page’s seal.

      proving…

      Seal sha256(name|slug|blurb): 15723ebbe4fdbf3af5616c23a4b9cd608471d35d3e96b272b2974e427e17250d

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