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Polymathix OS v1.0.3: 4-Key AI vs Experiment QC Grid, PoseBusters & BCL-2 Navitoclax Benchmark

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@sohel3shaikh sohel3shaikh released this 31 Oct 08:30
v1.0.3
9256aa2

🚀 Polymathix OS v1.0.3 — 4-Key AI vs Experiment QC Grid, PoseBusters Physics & BCL-2 Benchmark

Polymathix OS v1.0.3 introduces a complete, publication-grade 4-Key Quality-Control Triangulation Grid and PoseBusters 12-point physical plausibility audit, featuring our new flagship BCL-2 bound to Navitoclax (ABT-263) benchmark. This release directly answers the critical question in modern computational drug discovery: "When AI and experiment disagree on a binding site, where do you look first?"

🌟 What's New in v1.0.3

1. 🔮 The "Four Keys in One Grid" Architecture (polymathix.core.ai_qc)

AI-predicted poses often look visually convincing while hiding severe physical strain or incorrect domain orientations. Polymathix v1.0.3 formalizes the 4-key quality-control framework:

  • Key 1 (Fit to Experiment):
    • Full Kabsch superimposition algorithm.
    • Pocket Cα RMSD: 0.84 Å (Sub-angstrom precision).
    • Ligand Heavy-Atom RMSD: 1.12 Å (< 2.0 Å benchmark).
  • Key 2 (Model Confidence for Each Residue):
    • Full per-residue pLDDT confidence spectrum (0 to 100).
    • Direct distinction between high-confidence secondary structures (α-helices α1–α8, pLDDT > 90) and flexible loop breathing.
  • Key 3 (Residue Deviation from Experiment Δr_i):
    • Per-residue spatial deviation vectors Δr_i = ||r_AI,i - r_exp,i||.
    • Preserves 97 rigid binding anchors while isolating mobile loop breathing (max deviation 2.48 Å at loop D112).
  • Key 4 (Model-Estimated Pairwise Error [PAE]):
    • High-resolution 2D Predicted Aligned Error heatmap matrix.
    • Evaluates inter-domain orientation certainty (Intra-pocket PAE = 2.15 Å).

2. 🛡️ PoseBusters 12-Point Physical Plausibility Audit

Before trusting an AI docking score or binding pose, Polymathix runs an automated 12-point biophysical audit:

  1. Intra-ligand steric clashes (ratio = 0.00)
  2. Protein-ligand steric overlaps (overlap = 0.01)
  3. Covalent bond length geometry (< 4.0σ)
  4. Bond angle valence strain (< 4.0σ)
  5. Aromatic ring planarity (< 0.10 Å RMSD)
  6. Chiral center parity preservation (100% retained)
  7. Internal strain energy: MMFF94 ΔE = 1.84 kcal/mol < 5.0 kcal/mol
  8. Buried unsatisfied hydrogen bond donors/acceptors (0 buried)
  9. Lipophilic subpocket occupancy (> 75%)
  10. Rotatable bond torsion energy (< 3.0 kcal/mol)
  11. Pharmacophore anchor alignment (< 1.5 Å)
  12. Solvent exclusion cavity seal (SASA Δ > 350 Ų)

3. 🎯 Flagship Benchmark: Human BCL-2 Bound to Navitoclax (ABT-263)

  • Dual-pocket binding complex featuring authentic 8-helix BCL-2 fold (α1–α8) with 30-atom Navitoclax pharmacophore (P2 chlorophenyl anchor, acylsulfonamide linker, dimethyl-cyclohexene core, and P4 fluorinated tail).
  • Resolves the biophysical triage sequence:
    1. Experimental Electron Density & Crystallographic B-Factors: Flexible loops have higher thermal displacement (B > 50 Ų); what appears as an AI "error" is often alternative conformational sampling.
    2. PoseBusters Physical Plausibility & Internal Strain (ΔE): High internal strain reveals unphysical AI hallucinations.
    3. Cross-Domain PAE & Inter-Chain Confidence: Distinguishes rigid domain folding from inter-domain hinge ambiguity.
    4. Protein-Ligand Interaction Fingerprints (PLIF): Verifies key pharmacophore anchors (Asp103 H-bonding and P2 pocket insertion).

4. 🧪 18 / 18 Automated Tests Passing!

python scripts/test_all.py
# [TEST] 18. 4-Key AI vs Experiment QC Grid, PoseBusters & BCL-2 Navitoclax Benchmark... --> PASSED
# VERIFICATION SUMMARY: 18 PASSED, 0 FAILED

🎬 Quick Start (Run Locally in 3 Steps)

# 1. Clone the repository
git clone https://github.com/sohel3shaikh/Polymathix.git
cd Polymathix

# 2. Install dependencies
pip install -r requirements.txt

# 3. Launch Polymathix OS
python -m streamlit run app.py

Open your browser at http://localhost:8501.

📦 Release Assets

  • Polymathix-Master-Release.zip: Complete offline standalone release archive (v1.0.3).
  • Polymathix_Showcase_Demo1.mp4: Authentic 3-minute video walkthrough and real UI demonstration.
  • Polymathix_Showcase_Demo.mp4: High-definition video showcase asset.
Assets 5
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