STRC h01 Phase 9b Min-Relax Multi-Frame MM-GBSA Smoke 2026-04-27

STRC h01 Phase 9b — Min-Relax Multi-Frame MM-GBSA Smoke

Multi-frame min-relax MM-GBSA smoke preserves E1659A-favouring sign: 6 frames each, E1659A-minus-WT DELTA TOTAL -2.35 kcal/mol.

Problem

Phase 9b had moved from tooling/input failure to a one-frame minimized endpoint smoke. This proof asks whether the repaired matched WT/E1659A Amber inputs remain numerically stable across multiple relaxed frames, and whether the E1659A-favouring sign survives beyond one minimized endpoint.

Method

• Script: hypotheses/h01-pharmacochaperone/scripts/phase9b_minrelax_multiframe_smoke.py
• Input artifact: hypotheses/h01-pharmacochaperone/artifacts/phase9b_matched_holo_inputs/
• Output artifact: hypotheses/h01-pharmacochaperone/artifacts/phase9b_minrelax_multiframe_smoke/
• Conditions: matched WT and E1659A dry Amber complexes for v5.3__aq3__adamantyl__acylsulfonamide_SO2Me__-Cl.
• Sampling: 60 extra implicit-GB minimization steps from the repaired minimized complexes, writing frames every 10 steps.
• Restraint: protein :1-1775 restrained at 10 kcal/mol/A^2; ligand :1776 free.
• Endpoint score: MMPBSA.py generalized-Born rescoring (igb=5, saltcon=0.150) over all written frames.

Results

Condition	Frames	DELTA TOTAL mean	SD	SEM
WT	6	-15.8368	1.1186	0.4567
E1659A	6	-18.1832	0.2183	0.0891

E1659A-minus-WT DELTA TOTAL: -2.3464 kcal/mol.

Verdict

• Outcome: PASS as a compatibility/robustness smoke.
• Key number: E1659A-minus-WT DELTA TOTAL = -2.35 kcal/mol across 6 min-relax frames per condition.
• Interpretation: The repaired Amber inputs stay readable across multiple frames, and the E1659A-favouring sign survives short restrained relaxation.
• Limitations: These are restrained minimization-path frames, not equilibrated explicit-solvent holo MD. This result supports Phase 9b input/score sanity but does not replace production holo-MD MM-PBSA.

Ranking delta

• Hypothesis h01: tier A held | mech 4 held | deliv 3 held | misha_fit 4 held.
• Next step changes to: promote Phase 9b from smoke to production only if explicit-solvent holo MD / MM-PBSA reproduces the sign, or keep the min-relax result as a caveated robustness figure.

Connections

• [part-of] STRC h01 Phase 9b Holo MD MM-PBSA 2026-04-27 SKELETON
• [supports] STRC h01 Phase 9b Matched Amber Input Compatibility 2026-04-27
• [source] phase9b_minrelax_multiframe_smoke
• [see-also] phase9b_geometry_sanity