KRAS (isoform 2B) predicted structure via E8 lattice topological optimization (188 residues, UniProt P01116-2)

Description: Protein targetThis record contains the predicted 3D structure of human KRAS isoform 2B (UniProt P01116-2, 188 amino acids), generated using the E8 Navigator — a symmetry-based, non-data-driven protein folding method.MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPYIETSAKTRQGVEDAFYTLVREIRQHKLRKLNPPDESGPGCMSCKCVLS Biological relevanceKRAS is one of the most frequently mutated oncogenes in human cancer, particularly in lung adenocarcinoma where it is altered in ~25–30% of cases. The G12C mutation (glycine 12 to cysteine) is especially common and has become actionable with FDA-approved inhibitors (sotorasib, adagrasib). KRAS functions as a molecular switch cycling between GDP-bound (inactive) and GTP-bound (active) states, with conformational changes in the Switch I and Switch II regions driving downstream signaling. The C-terminal hypervariable region is intrinsically disordered and lipid-modified for membrane anchoring. Why this is a challenging folding problemDespite its relatively small size, KRAS is structurally subtle and difficult for conventional predictors: Flexible Switch I (30–40) and Switch II (60–76) regions adopt different conformations depending on nucleotide state The C-terminal tail (~170–188) is intrinsically disordered Oncogenic mutations (e.g. G12C) alter dynamics and pocket geometry in ways that are sensitive to small structural changes Standard tools like AlphaFold often favor one state (typically inactive) with high confidence but miss functional dynamics or produce low-confidence tails Method: E8 NavigatorThe structure was generated using the E8 Navigator, a topology-driven folding engine that maps the amino acid sequence onto the exceptional Lie group E8 lattice using physicochemical properties. Folding is performed as symmetry-constrained optimization on the E8 manifold, guided by a holographic coherence metric (Ψ) and convergence to ultra-low error states — without relying on multiple sequence alignments, neural networks, or PDB-derived patterns. ResultsThe output PDB (KRAS_E8_prediction.pdb) converged with Ψ ≈ 2.00 and very low final error, producing a compact G-domain with defined beta-sheet core, alpha-helices, and an extended/disordered C-terminal region. The nucleotide-binding pocket (including the P-loop and Switch regions) appears well-formed and free of major steric clashes.Ends at ~0.00002603 Å by step 1499 → Sub-picometer final error — extremely tight for a protein with flexible switch regions and a disordered tail. This suggests the method found a very low-entropy / high-symmetry configuration without major violations SignificanceKRAS is a critical test case for folding methods due to its biological importance and conformational subtlety. If the predicted structure aligns well with experimental GDP- or GTP-bound forms (e.g. PDB 4L9W, 7C40) — particularly in the active-site geometry and Switch regions — this demonstrates that higher-dimensional symmetry groups (E8) can capture functional protein folds in a manner orthogonal to current AI-based predictors. This approach may offer advantages for modeling mutation-sensitive or low-data proteins relevant to cancer biology. The prediction is provided openly for community inspection, comparison with experimental KRAS structures, and further evaluation of lattice-based folding methods. Files included KRAS_E8_prediction.pdb — full predicted structure (Optional: dashboard screenshot, convergence log excerpt)