STRC h01 Phase 9b-lite — Residue-Field Decomposition
Phase 9b-lite supports the broad electrostatic sign: E1659A-WT field delta +0.181 q/A at 18 A, p=1.5e-10; 9 A inner shell opposes.
Problem
Phase 9b proper is holo MD plus MM-PBSA, but gmx_MMPBSA is not installed in the local PATH yet. This smoke proof asks the tractable post-processing question first: using existing matched WT and E1659A MD snapshots, does the formal side-chain charge environment around the K1141 pocket independently preserve the E1659A > WT electrostatic sign without APBS grids, Vina scores, Boltz-2, or tauRAMD?
Method
- Script:
hypotheses/h01-pharmacochaperone/scripts/phase9b_lite_residue_field_decomposition.py - Inputs:
- WT ensemble:
models/artifacts/phase5a_snapshots/snap_000-019.pdb - E1659A ensemble:
models/artifacts/phase5d_snapshots/snap_000-019.pdb
- WT ensemble:
- Pocket center: centroid of K1141-ring C-alpha atoms from the existing h01 pocket definition: real residues 1141, 1135, 1137, 1165, 1167, 1175. WT ultra-mini residue numbers use the existing Phase 5a offset of -593.
- Charge proxy: one formal side-chain representative per charged residue: Lys NZ +1, Arg CZ +1, Asp CG -1, Glu CD -1. Histidine is omitted rather than assigning an ambiguous protonation state.
- Readout: sum q/r in e/A for charge representatives within sensitivity radii 9, 12, 15, 18, 21, and 24 A of the pocket center. Matched snapshots are compared by paired t-test.
Parameter provenance
| Parameter | Value | Source / rationale |
|---|---|---|
| Snapshot count | n=20 WT + n=20 E1659A | Existing Phase 5a / Phase 5d h01 MD ensembles. |
| Pocket ring residues | 1141, 1135, 1137, 1165, 1167, 1175 | Existing h01 K1141 pocket-ring definition used in Phase 5e / Phase 5k analyses. |
| WT residue offset | -593 | Existing Phase 5a ultra-mini construct numbering convention. |
| Radii | 9-24 A sensitivity grid | Method sensitivity sweep, not a biological constant. |
| Formal side-chain charges | Lys/Arg +1; Asp/Glu -1 | Standard formal-charge decomposition proxy; used only for sign / residue-field smoke, not physical free energy. |
Results
| Radius (A) | WT field q/A | E1659A field q/A | Delta MUT-WT q/A | paired t p | WT net q | MUT net q |
|---|---|---|---|---|---|---|
| 9 | -0.0271 +/- 0.0018 | -0.1120 +/- 0.0059 | -0.0849 +/- 0.0063 | 3.80e-11 | 0.00 | -0.95 |
| 12 | -0.1214 +/- 0.0020 | 0.0372 +/- 0.0104 | +0.1587 +/- 0.0109 | 9.61e-12 | -1.00 | 0.60 |
| 15 | -0.0731 +/- 0.0133 | 0.0079 +/- 0.0060 | +0.0810 +/- 0.0157 | 5.53e-05 | -0.30 | 0.15 |
| 18 | -0.0677 +/- 0.0074 | 0.1133 +/- 0.0125 | +0.1810 +/- 0.0146 | 1.54e-10 | -0.20 | 1.85 |
| 21 | -0.1721 +/- 0.0148 | 0.1645 +/- 0.0102 | +0.3366 +/- 0.0197 | 5.44e-13 | -2.30 | 3.00 |
| 24 | -0.3495 +/- 0.0076 | 0.1328 +/- 0.0102 | +0.4823 +/- 0.0141 | 1.56e-18 | -6.20 | 2.25 |
Artifacts:
hypotheses/h01-pharmacochaperone/artifacts/phase9b_lite_residue_field/phase9b_lite_residue_field.jsonhypotheses/h01-pharmacochaperone/artifacts/phase9b_lite_residue_field/radius_summary.csvhypotheses/h01-pharmacochaperone/artifacts/phase9b_lite_residue_field/per_snapshot_radius_fields.csvhypotheses/h01-pharmacochaperone/artifacts/phase9b_lite_residue_field/phase9b_lite_residue_field.md
Verdict
- Outcome: SMOKE_PASS for the broad charged-neighbourhood sign.
- Key number: 18 A shell delta = +0.1810 +/- 0.0146 q/A, paired p=1.54e-10.
- Interpretation: A force-field-light, APBS-independent decomposition preserves the main Phase 5k claim that the E1659A pocket neighbourhood is more favorable for an anion-like ligand than WT.
- Limitation: The 9 A inner shell opposes the sign. The mechanism is not a uniformly positive microenvironment; the supportive signal is a wider charged-neighbourhood effect from 12 A outward. This proof is not a physical binding free energy and does not replace 9b production MM-PBSA.
Ranking delta
- Hypothesis h01: tier A → A | mech 4 → 4 | deliv 3 → 3 | misha_fit 4 → 4.
- No hub frontmatter change. This is supportive orthogonal smoke evidence, not a production free-energy track.
- Next compute: keep Phase 9b production pending until
gmx_MMPBSAor an AmberTools MM-PBSA path is installed; meanwhile this result counts as a low-cost residue-decomposition cross-check, not one of the 5 production Phase 9 track verdicts.
Connections
[part-of]STRC h01 Phase 9 Orthogonal Cross-Checks Plan 2026-04-27[supports]STRC h01 Phase 9b Holo MD MM-PBSA 2026-04-27 SKELETON[supports]STRC h01 Phase 5k-WT Matched Ensemble APBS 2026-04-25[see-also]h01 hub[about]Misha