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

B-tier. Phase 1 ARM R-R hypothesis falsified; Phase 1c GREEN on secondary stump-cluster 1077-1114 with native C1081 disulfide-engineering geometry. Next: Phase 1d AF3 triple batch (A1078C / S1080C / S1579C homotypic + A1078W negative control) — user-invoked external AF3.

next-step tree

• Phase 1d AF3 PASS on any mutant (ipTM ≥0.50 + homodimer contacts ≥ WT) → A-tier → drop-in to h03 Ultra-Mini as engineered-avidity variant (zero payload cost)
• Phase 1d AF3 FAIL on all → C-tier (disulfide branch killed; no further compute)

Recent activity

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• h26 log
• strc
• h26
• Phase 1c contact re-cluster: GREEN. DBSCAN eps=6.5 Å on Ultra-Mini homodimer CIF found 3 clusters. Cluster 1 “stump” 1077-1114 (25 residues, 21 Cb-Cb disulfide geometries) ENTIRELY outside Phase 1 target 1579-1581. Native C1079+C1081 on both chains sit 6.87-7.09 Å from A1078/S1080 on opposing chain → single A1078C or S1080C engineers inter-chain disulfide without changing cystine count. Cluster 2 ARM has homotypic S1579C/S1579C at Cb-Cb 6.94 Å (re-opens Phase 1 target with disulfide chemistry). B held pending Phase 1d AF3 triple batch (A1078C + S1080C + S1579C homotypic + A1078W negative control). Promotion path: Phase 1d ipTM ≥0.50 + homodimer contacts ≥ WT → A-tier → drop into h03 Ultra-Mini as engineered-avidity variant (zero payload cost). → STRC h26 Phase 1c Contact Re-Cluster 2026-04-23
• Added to register: A-tier, Mech 4, Deliv 5, Misha 4. R-R repulsion at ARM 1579-1581 identified as dimer destabilizer → STRC Engineered Homodimer Avidity

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 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 + S1579F
• af3_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

log

h26 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