h26 — Engineered Homodimer Avidity
mech. Single-point mutation at Ultra-Mini homodimer interface (ARM 1579-1581) tested for dimer stabilization; Phase 1 AF3 FAILED — all 4 mutants destabilize dimer further, R-R repulsion hypothesis falsified. delivery. Would be drop-in to h03 Mini-STRC AAV (Anc80L65 + B8-IgK-Ultra-Mini-WPRE3-bGH) if any mutant passed; currently none does. patient-fit. Misha-compatible by inheritance from h03; not independently therapeutic.
status
C-tier. Phase 1 ARM R-R hypothesis falsified; Phase 1c found plausible cysteine geometry, but Phase 1d AF3 closed the rescue path: A1078C / S1080C / S1579C homotypic candidates and A1078W negative control all fail G1. No further compute unless a new scaffold or interface appears.
next-step tree
- Phase 1d AF3 final: all candidates FAIL G1 → C-tier; disulfide branch killed; no further compute.
- Reopen only if a new scaffold/interface appears from outside this branch.
Gates
Discipline import from PeptAI 9-gate pipeline (see h26 Gate Pilot — PeptAI Discipline Import 2026-04-25). Only the structural and stability gates carry over; PeptAI’s ChEMBL baseline (G0) and ADMET stack (G6–G8) are designed for receptor-agonist peptide drugs in systemic circulation and do not apply to an intracellular protein-domain edit packaged in AAV.
| Gate | Check | Threshold | State |
|---|---|---|---|
| G1 | Structure quality (AF3) | ipTM ≥ 0.50 AND pTM ≥ 0.60 | FAIL — A1078C 0.25/0.39; S1080C 0.33/0.41; S1579C 0.23/0.39; A1078W 0.23/0.37 |
| G2 | Homodimer interface preservation | inter-chain contacts ≥ WT count; closest Cb-Cb < 8 Å | CLOSED — no contact parse justified after upstream G1 fail |
| G3 | Disulfide geometry | Cb-Cb 4.5–7.5 Å; χ_ss within native cystine range | PASS analytical (Phase 1c GREEN; stump cluster 1077-1114; ARM 1579 homotypic Cb-Cb 6.94 Å) |
| G4 | Interface energy | ΔΔG_dimer ≤ −2 kcal/mol vs WT monomer (PRODIGY / MM-GBSA) | CLOSED — no candidate passed G1 |
| G5 | MD stability | 100 ns explicit solvent; RMSD < 4 Å; disulfide intact ≥ 90% frames | CLOSED — no candidate passed G1 |
| G6–G8 | ADMET (PROSPERousPlus / OpenSol / ToxinPred3) | — | N/A — protein domain inside AAV payload, not a systemic peptide drug |
| G9 | Drop-in compatibility with h03 Ultra-Mini | combined-construct ipTM ≥ Phase 1d value; TMEM145 GOLD-pocket contacts preserved | CLOSED — downstream gate never opened |
Threshold rationale: G1 ipTM/pTM tracks Phase 1d’s existing pass criterion; G2 contact count chosen to make “preserve” mechanical, not eyeballed; G3 geometry already pre-screened analytically (Phase 1c); G4 ΔΔG ≤ −2 kcal/mol is a conservative engineered-stabiliser bar borrowed from MD literature on cystine-engineered miniproteins; G5 MD parameters chosen to fit available compute on the M5 Max within reasonable wallclock.
Recent activity
const p = dv.page(dv.current().file.folder + "/log.md")
if (p && p.file.lists.length) dv.list(p.file.lists.slice(0, 5).map(l => l.text))
else dv.paragraph("_(no log entries)_")- h26 log
- strc
- h26
- A1078C retrieved from AlphaFold Server: fold
/fold/27162e77fc95333e, archive saved asmodels/fold_engineered_homodimer_A1078C_afs.zip. Best model ranking_score 0.34, ipTM 0.25, pTM 0.39; all five A1078C models fail G1 (ipTM >= 0.50andpTM >= 0.60). Final Phase 1d set is now 4/4 FAIL: A1078C 0.25/0.39, S1080C 0.33/0.41, S1579C 0.23/0.39, A1078W negative control 0.23/0.37. No G2/G4/G5/G9 follow-up justified. Ranking delta: tier B → C | mech 2 held | deliv 5 held | misha_fit 4 held | next_step → paused; no further compute unless a new scaffold/interface appears. → STRC h26 Phase 1d AF3 Final 2026-04-27 - B-tier promotion triage: h26 is the only fast possible B-to-S candidate, but only through the still-missing A1078C Phase 1d AF3 result. Local search found no A1078C ZIP under Downloads/STRC; 3/4 preliminary jobs already fail G1. Tier B held; next_step sharpened to retrieve/finish A1078C, then either demote to C on FAIL or parse G2/G4/G5 before any h03 drop-in/wetlab claim. → STRC B-Tier Promotion Triage 2026-04-27
evidence
- STRC Engineered Homodimer Avidity — main hypothesis (R-R repulsion prediction, now falsified)
- STRC Engineered Homodimer Phase 1 Results — Phase 1 AF3 results: 4/4 mutants fail homodimer gate
- STRC h26 Phase 1d AF3 Final 2026-04-27 — Phase 1d AF3 final: A1078C/S1080C/S1579C/A1078W all fail G1; h26 B → C
- STRC Homodimer Interface From CIF — source: weak homodimer at ARM 1579-1581 identified
scripts
models/ (legacy pool — see STRC Computational Scripts Inventory § h26)
af3_jobs_2026-04-23d_engineered_homodimer_builder.py— 5 jobs: WT ref + R1581Y + R1581F + S1579W + S1579Faf3_jobs_2026-04-23d_engineered_homodimer_forensics.py— Phase 1 results parser (4 mutants × 1-2 seeds, gate evaluation)engineered_homodimer_phase1c_contact_cluster.py— DBSCAN 6.5 Å spatial re-cluster on Ultra-Mini homodimer inter-chain contacts; per-cluster disulfide Cb-Cb scan 4.5-7.5 Å + mutation candidate ranking (steric / electrostatic / covalent)
artifacts
hypotheses/h26-engineered-homodimer/artifacts/phase1_af3_2026-04-23/ — 6 AF3 runs (4 mutants + 2 restart seeds) + analysis_summary.json
models/fold_engineered_homodimer_A1078C_afs.zip — A1078C Phase 1d AFS archive, fold 27162e77fc95333e
log
cross
- STRC Mini-STRC Single-Vector Hypothesis — h26 is a direct enhancement of h03 clinical candidate
- STRC Homodimer Interface From CIF — source analysis that identified the interface
Connections
[part-of]STRC Hypothesis Ranking[about]Misha