Production docking: prep helps (7.9->4.8A) but Vina wrong tool for sickle

§12.4 pushed to its limit. Meeko ligand prep + in-place symmetry RMSD
(spyrmsd, not obrms) on clean HDAC2/vorinostat: 7.9A -> 4.76A. Prep and
metric mattered, but still FAIL.

Residual cause is fundamental: vorinostat binds via hydroxamate-Zn
chelation and Vina has no metal-coordination term. Real finding: sickle's
druggable targets bind via non-classical chemistry classical docking
handles poorly -- Hb (covalent), PKR (allosteric+cofactor), HDAC (Zn
chelation). Vina is the wrong tool for this target landscape.

Redirect: data-driven AF3-class co-folding (Boltz-2/Chai-1/DiffDock)
handles these modes -- the indicated next tool, gated by the 24GB local
memory ceiling (cloud GPU needed). The "GPU breaks all-local" §12.6
prediction is now the binding constraint of the track.

Adds: scripts/dock_production.py; deps meeko, spyrmsd, gemmi.

Co-Authored-By: Claude Opus 4.8 (1M context) <noreply@anthropic.com>

docs/structure_binding_notes.md

@@ -79,13 +79,35 @@ Likely causes (in priority order):
 but doesn't survive honest validation. Credible structure-based docking needs production prep
 tooling (Meeko/ADFR), which is the real next investment for this track.
 
+## Step 3 — production prep helps, but classical docking is the wrong tool here (2026-06-24)
+
+`scripts/dock_production.py`: Meeko ligand prep (proper rotatable-bond/AD typing) + in-place
+symmetry-corrected RMSD (spyrmsd, not obrms which superimposes). On the clean HDAC2/vorinostat
+target (Zn kept):
+
+- **7.9 Å → 4.76 Å** with proper ligand prep + correct metric. Prep and metric genuinely mattered.
+- But still FAIL (>2 Å). The residual is the deeper problem: **vorinostat binding is defined by its
+  hydroxamate chelating the catalytic Zn, and Vina has no metal-coordination term** — it cannot
+  score the interaction that determines the pose.
+
+**The real finding: sickle's druggable targets bind via non-classical chemistry that classical
+docking handles poorly** — Hb/voxelotor (covalent), PKR/mitapivat (allosteric + cofactor),
+HDAC/vorinostat (Zn chelation). This is the target landscape, not bad luck. AutoDock Vina is the
+wrong tool for it.
+
+**Redirect:** the modality that DOES handle covalent/metal/induced-fit binding is **data-driven
+AF3-class co-folding** (Boltz-2 / Chai-1 / DiffDock — they learn these modes from the PDB). That is
+the indicated next tool for this disease — and it's gated by the **24 GB local memory ceiling**
+(PLAN §12.6 pitfall 4): needs a cloud GPU or a bigger box. The "GPU breaks all-local" prediction is
+now the binding constraint of the whole track.
+
 ## Next steps
-- [ ] Install **Meeko** (+ reduce / pdb2pqr) and redo receptor+ligand prep; re-run redocking RMSD.
+- [ ] AF3-class co-folding on a GPU (Boltz-2 affinity / Chai-1 / DiffDock); redo the §12.4
-- [ ] Fix the RMSD metric (in-place, symmetry-corrected) to rule out a measurement artifact.
+  positive-control recovery test there — it should handle the metal/covalent modes Vina can't.
-- [ ] Only once redocking validates (<2 Å) are affinity scores trustworthy — then cross-dock /
+- [ ] (optional) Salvage one classical Vina case: PKR with FBP/Mg cofactors RETAINED, to confirm
-  screen the library and revisit ligand-efficiency / pose-based scoring.
+  the harness can validate on a non-metal sickle target.
-- [ ] Later: AF3-class co-folding (Boltz-2/DiffDock via PyTorch-MPS — 24 GB ceiling) and the §12.9
+- [ ] Production receptor prep (Meeko mk_prepare_receptor + protonation) if staying with Vina.
-  generative beacon.
+- [ ] §12.9 generative beacon — only after a validated scoring function exists.
 
 > **Hardware note:** this machine is **24 GB** unified memory (not the 96 GB PLAN §2 assumed),
 > which caps local AF3-class model inference. Classical docking (above) is unaffected.

scripts/dock_production.py

@@ -0,0 +1,83 @@
+"""Push docking to credibility: Meeko ligand prep + in-place spyrmsd, on the clean HDAC2 target.
+
+Isolates the two cheap suspects behind the 7.9 A redocking failure:
+  1. ligand prep — replace bare obabel --gen3d with Meeko (correct rotatable bonds / AD typing)
+  2. RMSD metric — replace obrms (superimposes) with spyrmsd in-place, symmetry-corrected
+Receptor reused (obabel-protonated 4LXZ with catalytic Zn kept). If redock RMSD drops <2 A, the
+docking pipeline is validated and the earlier failure was prep+metric, not docking itself.
+"""
+
+from __future__ import annotations
+
+import subprocess
+from pathlib import Path
+
+import numpy as np
+from rdkit import Chem, RDLogger
+from rdkit.Chem import AllChem
+from meeko import MoleculePreparation, PDBQTWriterLegacy
+from spyrmsd import io as spyio, rmsd as spyrmsd
+
+import sys
+sys.path.insert(0, str(Path(__file__).resolve().parent.parent))
+from scripts.dock_positive_controls import STRUCT, VINA, WORK, pubchem_smiles  # noqa: E402
+from scripts.dock_validate import dock_pose, extract_crystal_ligand  # noqa: E402
+
+RDLogger.DisableLog("rdApp.*")
+PDB, RES, DRUG = "4LXZ", "SHH", "vorinostat"
+
+
+def prep_receptor_keep_zn() -> tuple[Path, np.ndarray, np.ndarray]:
+    atoms, lig, chosen = [], [], None
+    for ln in (STRUCT / f"{PDB}.pdb").read_text().splitlines():
+        if ln.startswith("ATOM") or (ln.startswith("HETATM") and ln[17:20].strip() == "ZN"):
+            atoms.append(ln)
+        elif ln.startswith("HETATM") and ln[17:20].strip() == RES:
+            key = (ln[21], ln[22:26]); chosen = chosen or key
+            if key == chosen:
+                lig.append(ln)
+    recpdb = WORK / f"{PDB}_rec.pdb"; recpdb.write_text("\n".join(atoms) + "\nEND\n")
+    recpdbqt = WORK / f"{PDB}_rec.pdbqt"
+    subprocess.run(["obabel", str(recpdb), "-O", str(recpdbqt), "-xr", "-p", "7.4"], capture_output=True)
+    xyz = np.array([[float(l[30:38]), float(l[38:46]), float(l[46:54])] for l in lig])
+    return recpdbqt, xyz.mean(0), np.clip((xyz.max(0) - xyz.min(0)) + 8, 16, 26)
+
+
+def meeko_ligand(smiles: str) -> Path:
+    mol = Chem.AddHs(Chem.MolFromSmiles(smiles))
+    AllChem.EmbedMolecule(mol, randomSeed=0xC0FFEE)
+    AllChem.MMFFOptimizeMolecule(mol)
+    setups = MoleculePreparation().prepare(mol)
+    pdbqt, ok, err = PDBQTWriterLegacy.write_string(setups[0])
+    if not ok:
+        raise RuntimeError(f"meeko ligand prep failed: {err}")
+    out = WORK / f"lig_{DRUG}_meeko.pdbqt"; out.write_text(pdbqt)
+    return out
+
+
+def inplace_rmsd(crystal_pdb: Path, docked_pdbqt: Path) -> float:
+    cref = WORK / "xtal.sdf"; cdoc = WORK / "docked.sdf"
+    subprocess.run(["obabel", str(crystal_pdb), "-O", str(cref)], capture_output=True)
+    subprocess.run(["obabel", str(docked_pdbqt), "-O", str(cdoc), "-f", "1", "-l", "1"], capture_output=True)
+    ref, mol = spyio.loadmol(str(cref)), spyio.loadmol(str(cdoc))
+    ref.strip(); mol.strip()
+    r = spyrmsd.rmsdwrapper(ref, mol, symmetry=True, minimize=False)
+    return float(r[0] if isinstance(r, (list, tuple, np.ndarray)) else r)
+
+
+def main() -> None:
+    rec, center, size = prep_receptor_keep_zn()
+    smi = pubchem_smiles(DRUG)
+    lig = meeko_ligand(smi)
+    print(f"meeko ligand pdbqt: {lig.name}; box center {center.round(1)} size {size.round(1)}")
+    pose = dock_pose(rec, lig, center, size)  # writes WORK/redock_out.pdbqt
+    raw = WORK / "redock_out.pdbqt"
+    xtal = extract_crystal_ligand(PDB, RES)
+    rmsd = inplace_rmsd(xtal, raw)
+    verdict = "PASS (<2A)" if rmsd < 2 else ("MARGINAL (<3A)" if rmsd < 3 else "FAIL")
+    print(f"\nvorinostat -> HDAC2 redock | in-place spyrmsd RMSD = {rmsd:.2f} A  {verdict}")
+    print("(prior obabel-ligand + obrms gave 7.9 A)")
+
+
+if __name__ == "__main__":
+    main()