diff --git a/docs/DISCOVERY_PREDICTION.md b/docs/DISCOVERY_PREDICTION.md index b2c79a3b..4aa8bd67 100644 --- a/docs/DISCOVERY_PREDICTION.md +++ b/docs/DISCOVERY_PREDICTION.md @@ -803,6 +803,11 @@ No biological activity has been demonstrated. The lab is the judge.* --- +**Tracking note (post-PR #101):** EXPERT_REVIEW_PACK.md: SEED-007 and SEED-005 reviewer notes +added (parallel to SEED-008/009 notes already present); SEED-007 Met oxidation risk row added +to Pipeline Limitations table. All 7 families now have equal depth in both the wet-lab handoff +and the expert review pack. + **Tracking note (post-PR #100):** WET_LAB_HANDOFF.md completed with dedicated special notes sections for all 7 seed families: SEED-007 (bombolitin-II, 4 pilot candidates, all NOVEL, best serum stability 0.636–0.662, primary breakthrough candidate VAR_009 at ensemble 0.849), diff --git a/docs/EXPERT_REVIEW_PACK.md b/docs/EXPERT_REVIEW_PACK.md index c7648a2d..28b6151f 100644 --- a/docs/EXPERT_REVIEW_PACK.md +++ b/docs/EXPERT_REVIEW_PACK.md @@ -175,6 +175,23 @@ not a claim that they are inactive. | SEED-008 (Trp-rich) | 4 | Indole ring stacking; not helical | Genuine (✓ NOVEL) | Moderate (13 AA model edge) | ~70–82% | Novel mechanism; high disagreement | | SEED-009 (Pro-rich) | 4 | Ribosome exit + DnaK | Genuine (✓ NOVEL) | **Best** (Pro-X bonds resist protease) | ~60–75% | Novel; run RPMI parallel | +**SEED-007 reviewer note:** Bombolitin-II (*Megabombus pennsylvanicus* venom) is the +**largest selected family** (26 variants, 4 pilot slots). All 4 pilot candidates are NOVEL +and occupy ranks 3, 4, 5, and 8 in the panel, making SEED-007 the family with the most +top-10 placements. SEED-007_VAR_009 (ensemble 0.849) is the primary bombolitin breakthrough +candidate. **Critical synthesis note:** all 4 pilot variants contain Met at position 6 — +request Nle (norleucine) substitution or argon atmosphere storage; HPLC purity mandatory at +receipt. Serum stability model scores (0.636–0.662) are the best raw scores among all NOVEL +pilot families (tied with SEED-006). If SEED-007 variants are active, compare MIC to parent +Bombolitin-II (IKFTTMLKKLG) — any single-substitution improvement is a direct SAR finding. + +**SEED-005 reviewer note:** Cecropin-magainin hybrid (KRLFKKIGSALKFL, 14 AA). Only 1 pilot +slot (rank 19); classified CLOSE_RELATIVE (60% similarity to a reference AMP). This family +is the **lowest-priority NOVEL candidate** in the pilot panel — if synthesis budget must be +reduced, SEED-005 may be deferred while retaining SEED-006/007/008/009. If included, note +the lowest safety score in the panel (0.845); hemolysis assay at MIC/3 is mandatory, and +if HC₅₀ < 10× MIC the family should be deprioritised for Wave 2. + **SEED-008 reviewer note:** Disagreement is highest in panel (0.41–0.44) because the Boman index penalises Trp (hydrophobic), while the activity scorer rewards it (Trp-weighted aromatic bonus). For Trp-rich AMPs acting via indole ring insertion into the membrane, `activity_likeness` is the @@ -259,6 +276,7 @@ The expert reviewer must be aware of these limitations: | SEED-008 high disagreement (0.41–0.44) | Boman index penalises Trp; activity_likeness more appropriate for Trp-rich sequences | | Serum stability model calibrated for 18–30 AA | SEED-003 (11 AA) and SEED-008 (13 AA) scores may underestimate actual stability | | Pro-rich serum stability not in model | SEED-009 model scores (0.572) expected to underestimate actual stability; Pro-X bond resistance is mechanistic | +| SEED-007 Met oxidation (all 4 pilot variants) | Met at position 6 in all SEED-007 pilot sequences; oxidised Met loses amphipathicity; Nle substitution or argon storage required | | Novelty vs. 45 seeds only (pipeline) | Broad check vs 72-AMP DB done (PR #86); APD3 BLASTp still recommended before publication | | Conservative generation only | Near-seed variants; genuinely novel families not explored by de novo generation | | No structural prediction | No secondary structure, membrane interaction, or 3D modeling | diff --git a/docs/ROADMAP.md b/docs/ROADMAP.md index f142c576..8bad53c0 100644 --- a/docs/ROADMAP.md +++ b/docs/ROADMAP.md @@ -85,6 +85,7 @@ Implemented during the pre-wet-lab improvement loop (PRs #31–#54): - Discovery prediction tracked through PRs #92–#95 in DISCOVERY_PREDICTION.md (PR #96) - WET_LAB_HANDOFF.md: version tag corrected, PROLINE_RICH_INTRACELLULAR QC flag table row, `amphipathic_score`/`charge_ph74` score reference table rows added (PR #97) - EXPERT_REVIEW_PACK.md: note added on new CSV columns for within-family prioritization (PR #98) +- EXPERT_REVIEW_PACK.md: SEED-007 reviewer note (Met oxidation, bombolitin origin, SAR framing, top-10 slots) and SEED-005 reviewer note (lowest priority, safety margin) added; SEED-007 Met oxidation row in Pipeline Limitations table (PR #101) - WET_LAB_HANDOFF.md completed with dedicated special notes for all 7 seed families: SEED-007 (bombolitin-II, 4 pilot slots, all NOVEL, best serum stability, Met oxidation guidance, breakthrough-candidate framing), SEED-005 (cecropin-magainin hybrid, safety/serum risk note), SEED-008 (puroindoline-a, Trp aggregation handling, aromatic-mechanism CD interpretation), SEED-009 (Bac2A proline-rich, Pro coupling guidance, RPMI-parallel assay note restated as standalone); Serum Stability section header updated to "All 7 Seeds" with SEED-006 and SEED-007 table rows added; DISCOVERY_PREDICTION.md tracking updated (PR #100) ## v1.0 — Validated dry-lab-to-wet-lab loop