{
  "version": 3,
  "created_at": "2026-07-09T00:34:03.026Z",
  "task_summary": "Re-engineer the Tier-2 protein binders into gut-restricted, protease-stable formats",
  "agents": [],
  "phases": [
    {
      "name": "Plan",
      "delegations": [
        {
          "steps": [
            {
              "title": "Map protease liabilities on both binders",
              "description": "For the best MICA-decoy and IL-15 binder sequences, apply PeptideCutter-style cleavage rules for the major GI proteases (pepsin, trypsin after K/R-not-before-P, chymotrypsin after F/Y/W/L/M, elastase after A/V/G/S/I/L) to enumerate every predicted cut site. Cross-reference against the fixed interface residue positions (29 for MICA-decoy, 12 for IL-15 binder). Save celiac_binder_protease_map.csv (per-position: residue, proteases cutting, in-interface flag)."
            },
            {
              "title": "Protease-harden the sequences (interface-preserving)",
              "description": "Reduce protease liability by substituting cleavage-prone residues OUTSIDE the fixed interface with protease-resistant alternatives (K/R→Q/A where surface, aromatic→non-aromatic where non-core), then re-run SolubleMPNN with the union of {interface residues + newly-fixed anti-protease positions} held fixed so the rest re-optimizes for stability. Verify all interface residues remain unchanged. Save hardened sequences to celiac_binder_hardened.csv + FASTA."
            },
            {
              "title": "Gut-stability / developability scorecard",
              "description": "Score native vs SolubleMPNN vs protease-hardened variants on: predicted cleavage-site count per protease, cysteine/disulfide count (stability), net charge and pI, aromatic content, length. Quantify the protease-site reduction achieved. Save celiac_binder_developability.csv."
            },
            {
              "title": "Delivery-format design spec",
              "description": "Specify the gut-restriction engineering path for each binder: (a) VHH/single-domain reformatting rationale (acid + protease stability, ~13 kDa, non-absorbed), (b) mucin/epithelium-anchoring options (e.g. CBM/mucin-binding fusion), (c) non-absorption argument (size + charge), (d) the surface-vs-deep target-depth assessment (NKG2D-MIC and IL-15 both act at the epithelial surface — favorable). Save celiac_binder_delivery_spec.json + prose."
            },
            {
              "title": "Design figures",
              "description": "With figure-style: (a) protease-liability map along each sequence with interface residues and cut sites marked; (b) before/after hardening bar (cleavage sites per protease, native vs hardened); (c) format/delivery schematic (current scaffold → VHH-graft → mucin-anchored gut-restricted format). Publication-grade, non-overlapping labels. Save the PNGs."
            },
            {
              "title": "Consolidated design report",
              "description": "Write celiac_gut_restricted_binder_report.md: what was hardened and by how much, interface integrity confirmation, the delivery-format path, honest validation-status section (CPU-only: no fold/co-fold, VHH graft is specified not modeled), and GPU next-steps. Bundle all artifacts."
            }
          ]
        }
      ],
      "id": "phase-0"
    }
  ],
  "desired_outputs": [
    "Protease-liability map for both binders (MICA-decoy + IL-15 binder) with per-site cleavage annotation",
    "Protease-hardened sequence variants preserving the fixed binding interfaces",
    "Gut-stability / developability scorecard (protease sites, disulfides, charge, format)",
    "Delivery-format design spec (VHH reformatting path, mucin-anchoring, non-absorption rationale)",
    "Design figures (protease map, before/after hardening, format schematic)",
    "Consolidated gut-restricted-binder design report"
  ],
  "feasibility": {
    "rationale": "Protease-cleavage mapping (trypsin/chymotrypsin/pepsin/elastase rules) and interface-preserving mutation are pure sequence/structure analysis, fully CPU-feasible with the existing designs and interface residue sets already in hand. ProteinMPNN and the design env are already set up. The ceiling is honest: no GPU means no folding/co-fold validation of the hardened variants and no de novo VHH-graft structure prediction — the VHH reformatting is delivered as a specified engineering path plus sequence-level analysis, not a folded model. Wet-lab protease-resistance and binding remain to be tested.",
    "confidence": "high"
  }
}