Pharmacochaperone (h01) — parameter provenance
Source agent: h01 audit (Sonnet 4.6), 2026-04-23. Consumer: all 17 pharmacochaperone_*.py scripts in models/.
Parameter table
| Parameter | Value used | Units | Source | Page/section | Status | Script(s) | Action |
|---|---|---|---|---|---|---|---|
| Water probe radius | 1.4 | Å | Physical constant (Lee & Richards 1971) | standard | ✅ physical | phase1_mutant_pocket | None |
| Carbon vdW radius | 1.7 | Å | Physical constant (Bondi 1964) | standard | ✅ physical | phase1_mutant_pocket | None |
| Salt-bridge O-N distance | 2.8 | Å | Physical constant (Hubbard geometry) | standard | ✅ physical | phase3c_shape_fit | None |
| K-to-kJ conversion | 1/4.184 | — | Physical constant | — | ✅ physical | phase4f | None |
| Water dielectric constant | 78.5 | — | Physical constant | — | ✅ physical | phase4f (eps_solvent) | None |
| pLDDT threshold | 70 | — | Standard AF2/AF3 convention (Jumper 2021 Nature) | — | ✅ standard | phase1b | None |
| AmberFF19SB | — | — | He 2020 JCTC | — | ✅ standard MD | phase5 | None |
| GAFF2 | — | — | Wang 2004 JCCA | — | ✅ standard MD | phase5 | None |
| TIP3P water | — | — | Jorgensen 1983 JCP | — | ✅ standard MD | phase5 | None |
| NaCl concentration | 0.15 | M | Physiological | — | ✅ standard | phase5 | None |
| Rule-of-3 (Congreve): MW<300, logP<3, HBD≤3, HBA≤3, rot≤3 | — | — | Congreve 2003 Drug Discov Today | — | ✅ standard (textbook) | phase3b | Optional citation note |
| Docking box size | 18×18×18 | Å | In-silico: Phase 2B subpocket volume → box calibrated to 159 ų pocket | — | ✅ in-silico | target_prep, phase4_common | None |
| K1141-NZ to F1646-ring distance | 5.69 → 5.7 | Å | In-silico: measured from AF3 WT CIF | Phase 3A | ✅ in-silico | phase3b | None |
| Reference ΔΔG gap | 8.4 | kcal/mol | In-silico: STRC Electrostatic Analysis E1659A (multi-method PAE-corrected) | own note | ✅ in-silico | phase4f (REFERENCE_GAP_KCAL_MOL) | Add # see STRC Electrostatic Analysis E1659A comment |
| Druggability threshold (Phase 4a gate) | ≥0.70 | 0-1 | In-silico: calibrated to Phase 0 result (0.86 WT) | Phase 0 | ✅ in-silico | phase4a | None |
| ΔΔG gate (WT vs MUT docking) | 1.0 | kcal/mol | In-silico: ~2× Vina paired noise (0.5-0.8 kcal/mol) | phase4c comment | ✅ in-silico | phase4c | None |
| K1141A score-loss gate | ≥2.0 | kcal/mol | In-silico: 2× DELTA_GATE, conservative pharmacophore falsification | — | ✅ in-silico | phase4d | None |
| Vina exhaustiveness | 32 | — | Standard Vina: 4× default (8), conservative for small pocket | Trott 2010 JCIM | ✅ standard | phase4b | Optional: cite Trott 2010 / Eberhardt 2021 |
| Vina score threshold (diflunisal gate) | ≤−5.0 | kcal/mol | In-silico heuristic (conservative relative to diflunisal ~−12 kcal/mol real TTR affinity) | — | ⚠ no citation | phase4b | NEEDS citation: Eberhardt 2021 JCIM (Vina 1.2 CASF benchmark) |
| MM-PBSA ΔG_bind gate | ≤−6.0 | kcal/mol | In-silico heuristic | — | ⚠ no citation | phase5 | NEEDS citation: Genheden & Ryde 2015 Expert Opin Drug Discov |
| RWM PK envelope: MW 250-400 Da, LogP 1.5-3.5, HBD 0-2 | per range | — | 2018-salt-plontke-pharmacokinetic-principles-inner-ear | Fig 4, Table 2 | ✅ paper in strc/papers/ | target_prep docstring | Add # Salt & Plontke 2018 comment in script |
| TPSA filter for delivery | 40–90 | Ų | UNLABELED in script — hypothesis note says 70–100 per Salt & Plontke 2018 | — | ⚠ INCONSISTENCY: CNS range used instead of RWM range | phase3b | TIGHTEN to 70–100 per 2018-salt-plontke-pharmacokinetic-principles-inner-ear |
| MW filter for virtual screen | 180–350 | Da | UNLABELED — hypothesis note says 200–500 | — | ⚠ INCONSISTENCY | phase3b | Harmonize with hypothesis note |
| Druggability v_opt | 250–300 | ų | In-house heuristic (loosely SiteMap-inspired) | — | ⚠ inconsistent across phases | phase2 (300), phase2b (250) | Label “in-house” or cite Halgren 2009 SiteMap |
| Druggability composite weights | 0.5/0.3/0.2 (p1), 0.4/0.25/0.2/0.15 (p2), 0.3/0.2/0.15/0.15/0.2 (p2b) | — | In-house — three different schemes | — | ⚠ undocumented inconsistency | phase1, phase2, phase2b | Document rationale or harmonize in one function |
| MM-GBSA recovery gate | ≥30% of 8.4 kcal/mol | — | Clinical analogy: VX-809 restores ~30% CFTR function | Bulawa 2012 PNAS | ✅ clinical analogy — defensible | phase4f (RECOVERY_GATE) | None; note already references Bulawa class implicitly |
Red flags
MEDIUM priority
1. TPSA filter 40–90 Ų in phase3b (should be 70–100 Ų)
- Script uses CNS-delivery TPSA range; intratympanic/RWM delivery requires 70–100 Ų per Salt & Plontke 2018.
- The correct paper IS in strc/papers/. Fix: change filter, add comment
# Salt & Plontke 2018 RWM PK envelope. - Risk: compounds with TPSA 40–70 Ų may not cross RWM but pass the virtual screen. Three phase3b results could be artifacts.
2. Inconsistent druggability scoring weights across three scripts
- phase1_mutant_pocket:
0.5 vol + 0.3 hp + 0.2 hb - phase2_pocket_scan:
0.40 vol + 0.25 hp + 0.20 r + 0.15 hb - phase2b_subpockets:
0.30 v + 0.20 h + 0.15 r + 0.15 hb + 0.20 depth - Impact: druggability scores from Phase 1 are NOT comparable to Phase 2 or 2B. Phase 4a threshold of 0.70 was set based on Phase 0 (Phase 2B formula), but Phase 1 uses a different formula. Scripts are used for internal scoring only, not cross-phase numeric comparisons, so operational impact is low — but misleading if compared.
LOW priority
3. Vina −5 kcal/mol gate (phase4b) lacks citation
- Reasonable conservative value but needs reference to Vina benchmark papers for reviewer defense.
4. MM-PBSA −6 kcal/mol gate (phase5 scaffold) lacks citation
- MM-PBSA thresholds are not transferable across targets; should be labeled as pipeline-specific empirical gate.
5. MW filter 180–350 Da inconsistent with hypothesis note (200–500 Da)
- Low risk: tighter range is more conservative for fragment screening. Acceptable if documented.
No phantom citations found
Unlike h09, h01 scripts contain zero fabricated paper citations. No “Salt 2011” style phantom references. Every numeric constant traces to either a physical constant, an in-silico output, a standard community convention, or a real paper already in strc/papers/. The issues above are internal inconsistencies and missing attribution notes — not citation fabrications.
Connections
[part-of]_hub (literature-params)[see-also]2018-salt-plontke-pharmacokinetic-principles-inner-ear — RWM PK envelope (needed for TPSA fix)[see-also]STRC Electrostatic Analysis E1659A — source of 8.4 kcal/mol reference gap[see-also]STRC Pharmacochaperone Virtual Screen E1659A — main h01 hypothesis note[applies]STRC Hypothesis Ranking (h01, A-tier)