STRC Pharmacochaperone Loop 1642-1651 Target
E1659A does not abolish a salt bridge — it rearranges a proline-rich loop (L1642-P-G-G-F-G-P-G-N1651) by ~3 Å across 10 contiguous high-confidence residues. This loop, not the mutation site itself, is the pharmacochaperone target. Class: VX-809-style tertiary-fold stabilizer (not VX-770-style interface rescuer).
Alignment correction was load-bearing
Initial Kabsch superposition of AF3 Job 3 (MUT) onto Job 4 (WT) gave global RMSD 14.9 Å — an artifact of including disordered low-pLDDT tails in the anchor. Re-aligning on 1050 common residues with pLDDT ≥ 70 collapses global RMSD to 4.84 Å and reveals a clean 2.71 Å local RMSD in the 10 Å shell around E1659 (27 residues).
pLDDT around E1659: 93.4 WT / 93.2 MUT. AF3 is confident about both folds — the 2.7 Å rearrangement is real structural consequence, not prediction noise.
K1141 displaces 3.38 Å
E1659(OE)→K1141(NZ) in WT = 9.81 Å — too far for a direct Coulomb contact, but within Bjerrum length for long-range electrostatic coupling. When E→A is introduced, K1141 NZ moves 3.38 Å after proper alignment. The “salt bridge” was actually an electrostatic tether shaping neighbouring loop geometry.
Acidic triad E1655-E1659-E1164 is not a Ca²⁺ site
Pairwise distances 9.9 / 12.6 / 11.1 Å. All >8 Å, so no EF-hand-class Ca²⁺ coordination possible (requires 3-4 Å carboxylate spacing). Rules out a Ca²⁺-mimetic pharmacochaperone strategy.
The loop is the real mutation-responsive region
Top-displaced high-confidence (pLDDT ≥ 85) residues within ±30 of E1659:
| Residue | Type | ΔCα (Å) | pLDDT WT / MUT |
|---|---|---|---|
| G1644 | GLY | 3.60 | 85 / 85 |
| P1643 | PRO | 3.60 | 86 / 86 |
| L1642 | LEU | 3.31 | 92 / 92 |
| G1647 | GLY | 3.27 | 93 / 92 |
| G1645 | GLY | 3.25 | 90 / 89 |
| F1646 | PHE | 3.15 | 92 / 92 |
| N1651 | ASN | 3.08 | 92 / 92 |
| P1648 | PRO | 3.04 | 93 / 93 |
Ten contiguous high-confidence residues shift ~3 Å — this is a real, localised loop displacement, not a tail flap.
Druggability at the mutation site itself is marginal
At the E1659 position (8 Å shell): druggability score 0.53 for both WT and MUT; volume score only 0.1 (pocket too tight, no void expansion from E→A — Δvoid = +0.5 ų). The mutation site alone is NOT a viable binding pocket. The drug must engage the loop surface allosterically.
Implication for drug class
- Primary target: the proline-rich loop 1642-1651, not the E1659 side-chain position
- Small-molecule action: stabilise loop in WT-like conformation against the displacement induced by losing the E1659 anchor
- K1141 position is a useful QSAR readout: compounds that preserve K1141 geometry in MUT simulation are candidates
- Class: VX-809 tertiary-fold stabiliser, not VX-770 interface rescuer
- Next step: cavity search on WT near the loop → see STRC Pharmacochaperone K1141 Fragment Pocket
Files / Models
~/STRC/models/pharmacochaperone_phase1_mutant_pocket.py— initial scan (alignment artifact; retained for audit)~/STRC/models/pharmacochaperone_phase1b_highconf_realign.py— corrected pLDDT-weighted Kabsch alignment~/STRC/models/pharmacochaperone_phase1b_results.json— load-bearing numbers (RMSD, K1141 displacement, loop residue shifts)~/STRC/models/pharmacochaperone_phase1b.png— figure
Connections
[part-of]STRC Pharmacochaperone Virtual Screen E1659A — parent hypothesis this finding refines[see-also]STRC Pharmacochaperone K1141 Fragment Pocket — follow-up cavity scan using this loop as anchor[see-also]STRC Electrostatic Analysis E1659A — original 49.8 ų cavity / salt-bridge calculation this work supersedes in mechanism[see-also]STRC E1659A Conservation and Reclassification — reclassification from “null” to “misfolded fully-expressed” that makes pharmacochaperone strategy viable[applies]Misha — Misha’s E1659A is the specific mutation modelled