Phase 7I Tier-1 pose ensemble stability
Method: K1141 NZ position read from each of 20 Phase 5d MD snapshots; ligand pose = Vina best pose against averaged structure (/Users/egorlyfar/STRC/models/docking_runs/8e_v5_2/poses); per-snapshot min distance from K1141 NZ to any ligand O atom.
K1141 NZ rigidity: radial drift 2.14 ± 0.81 Å (rigid pocket).
| Rank | Compound | Head | Boltz Δ | n O | mean K1141 NZ ↔ O (Å) | sd | range | call |
|---|---|---|---|---|---|---|---|---|
| Tier-1 | v5.2__aq3__1-indanyl__phosphonate__-CF3 | phosphonate | +0.067 | 3 | 4.41 | 0.86 | 3.55–5.27 | 🟢 Coulomb sink (4–8 Å) |
| Tier-1 | v5.2__aq3__adamantyl__CONHOMe__-Cl | CONHOMe | +0.066 | 2 | 3.89 | 0.73 | 3.16–4.61 | 🟢 salt-bridge zone (< 4 Å) |
| Tier-1 | v5.2__aq3__adamantyl__CONHOMe__-CN | CONHOMe | +0.065 | 2 | 4.21 | 0.76 | 3.45–4.97 | 🟢 Coulomb sink (4–8 Å) |
| Tier-1 | v5.2__aq3__4-F-biphenyl__phosphonate__-CN | phosphonate | +0.035 | 3 | 2.83 | 1.33 | 1.49–4.16 | 🟢 salt-bridge zone (< 4 Å) |
| Reference | v5.2__aq3__adamantyl__CONHOH__-Cl | CONHOH | -0.017 | 2 | 5.02 | 0.57 | 4.45–5.59 | 🟢 Coulomb sink (4–8 Å) |
Interpretation.
-
Coulomb sink (mean < 8 Å, ~3·Bjerrum length in 78ε water): formal-anion electrostatic attraction operative, consistent with Phase 5k mechanism (lead CONHO⁻ ↔ K1141 NZ +4.53 kT/e attractor).
-
Salt-bridge zone (mean < 4 Å): direct N–H…O contact with the K1141 NZ side-chain amine; APBS-correct rescore would bind this 2–3 kcal/mol tighter than Phase 5b Vina dG.
-
Outside Coulomb range (mean > 8 Å): Vina parked the ligand far from K1141 (Gasteiger-neutral-charge force-field artefact); mech 4 not directly operative on this geometry; need WT-MUT distinction by alternate mech driver (Boltz-2 detected one for CONHOMe / phosphonate per Phase 7I).