Pre-registered hypothesis and prediction record: recursive-collapse trace signature of protein structural bistability in tau and α-synuclein

Pre-registered hypothesis and prediction record for blind topological collapse analysis comparing native disease proteins and their aggregation-causing single-residue variants in two well-characterized neurodegenerative-disease protein systems, to be performed by the DON Research engine. Pre-registration locked on 2026-05-10; experiment will execute only after this record receives a CERN/Zenodo timestamp. Substrates pre-specified (variants will be constructed by single-residue substitution on the fetched native sequence at experiment time): - Pair A: tau (UniProt P10636, MAPT 2N4R isoform, 441 aa) vs tau-P301L (Pro→Leu at position 301; frontotemporal dementia variant, well-documented aggregation propensity) - Pair B: α-synuclein (UniProt P37840, 140 aa) vs α-synuclein-A53T (Ala→Thr at position 53; familial Parkinson's variant, well-documented aggregation propensity) Methodology: each substrate is fed as raw single-letter sequence into recursivecollapse (features, backbone=True, auditₗog=True, nodeₕistory=True) where features = [ord (c) for c in seq]. The engine state is locked at the current numpy path; no engine modification, no parameter tuning, no substrate re-selection between this pre-registration and execution. Disease-state labels (native vs aggregation-causing variant) are bookkeeping conventions external to the engine, which only ever receives the sequence as ASCII byte values. Canonical structural objects are extracted by tools/extractₚostcollapseₜargets. py with default arguments. Reference baseline (already observed in this lab on 2026-05-10, KRAS WT and four single-residue oncogenic variants run through identical pipeline configuration): - KRAS-WT (188 aa): terminates coherently at scale 38, closureₕorizon length=1, 3 polarityflipᵦones, 1 silencecorridor, anchorcore members at psi = −tanh (1. 0) = −0. 7616 and phicollapse native nₛcales (extended trajectory) 2. variant len (polarityflipᵦones) > native (more regime oscillations) 3. variant len (silencecorridors) > native (recurring loss of coherence) 4. variant closureₕorizon. length > native (delayed lock) 5. variant anchorcore has at least one member with phicollapse equal to ord (member. aa) within ±0. 5 (un-modulated kernel residue, signature of failure to coherently commit) Confirmation rule: H1 confirmed if BOTH pair A and pair B independently show variant strictly greater than native on at least 3 of the 5 metrics. Partially confirmed if exactly one pair satisfies the ≥3-of-5 criterion (reportable but requires additional substrate pairs before claiming generality). Falsified if neither pair satisfies, or if variants show MORE coherent terminations than natives. In all three outcomes the full canonical-objects output for all four substrates will be deposited as raw artifacts; no selective reporting. Files to be deposited POST-experiment alongside this pre-registration record: - tauₙativewithₕistory. json — tau MAPT 2N4R native engine output, full audit + nodeₕistory - tauₚ301lwithₕistory. json — tau P301L variant engine output, full audit + nodeₕistory - asynₙativewithₕistory. json — α-synuclein native engine output, full audit + nodeₕistory - asynₐ53twithₕistory. json — α-synuclein A53T variant engine output, full audit + nodeₕistory - tauₙativeₚostcollapseₜargets. json — canonical structural objects (anchorcore, polarityflipᵦones, silencecorridors, closureₕorizon, etc. ) for tau native - tauₚ301lₚostcollapseₜargets. json — same for tau P301L - asynₙativeₚostcollapseₜargets. json — same for α-synuclein native - asynₐ53tₚostcollapseₜargets. json — same for α-synuclein A53T - 2026-05-10PROTEINBISTABILITYPREREG. md — this pre-registration record, byte-identical to the version timestamped here This deposit externalizes the hypothesis and predictions BEFORE the experiment runs, providing a third-party-verifiable timestamp via Zenodo's CERN-backed archival infrastructure. The pre-registration is locked at this deposit's DOI. Any modification post-registration requires a new pre-registration record explicitly noting and superseding this one. The KRAS reference-baseline observations cited above were generated 2026-05-10 in the same lab session and are deposited separately (see kras_*withₕistory. json and kras_*ₚostcollapseₜargets. json artifacts). Limitations: this experiment is N=2 substrate pairs. The trace-layer pattern's statistical generality across the broader class of aggregation diseases (Alzheimer's amyloid-β, ALS TDP-43/SOD1, Huntington's polyQ, prion diseases, type-II diabetes IAPP, etc. ) cannot be claimed from these two pairs alone — extension to other systems requires its own pre-registration and its own deposit. The choice of P301L (over P301S, R406W, K280Δ for tau) and A53T (over E46K, H50Q for α-synuclein) is based on literature documentation depth, not on prior trace-layer evidence. The 5 comparison metrics were selected from patterns observed in the KRAS-WT vs KRAS-oncogenic-variant comparison; their generality across protein families is itself part of what the experiment tests. The KRAS reference baseline is N=1 protein system; the interpretation that KRAS-G12D/G12V's failure-to-terminate signature represents the same trace-layer phenomenon as bistability in aggregation diseases is the working hypothesis under test, not a previously-established result.