DOI: 10.5281/zenodo.18486905
title: Influenza A Hemagglutinin (HA) ectodomain prediction via E8 lattice topological optimization

description: Protein target

This record contains the predicted 3D structure of the hemagglutinin (HA) ectodomain from Influenza A virus (example: A/California/04/2009 H1N1pdm09 strain), generated using the E8 Navigator — a symmetry-based, non-data-driven protein folding method.MKANLLVLLCALAAADADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDSHNGKLCRLKGIAPLQLGKCNIAGWLLGNPECDPLLPVRSWSYIVETPNSENGICYPGDFIDYEELREQLSSVSSFERFEIFPKESSWPNHNTNGVTAACSHEGKSSFYRNLLWLTEKEGSYPKLKNSYVNKKGKEVLVLWGIHHPPNSKEQQNLYQNENAYVSVVTSNYNRRFTPEIAERPKVRDQAGRMNYYWTLLKPGDTIIFEANGNLIAPMYAFALSRGFGSGIITSNASMHECNTKCQTPLGAINSSLPYQNIHPVTIGECPKYVRSAKLRMVTGLRNIPSIQSRGLFGAIAGFIEGGWTGMIDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNTVIEKMNIQFTAVGKEFNKLEKRMENLNKKVDDGFLDIWTYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNGCFEFYHKCDNECMESVRNGTYDYPKYSEESKLNREKVDGVKLESMGIYQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI

Biological relevance

Hemagglutinin is the major surface glycoprotein of influenza viruses and the primary target for seasonal and pandemic influenza vaccines as well as neutralizing antibodies. HA mediates receptor binding and viral entry, undergoes dramatic conformational changes during membrane fusion, and is heavily glycosylated. Accurate structural modeling of HA is critical for understanding immune evasion, vaccine design, and antibody escape mechanisms.

Why this is a challenging folding problem

HA is structurally difficult for conventional prediction methods:



The ectodomain is large (~566 residues) with multiple subdomains, flexible loops, and heavy glycosylation that shields much of the surface

It exists in at least two major conformational states (pre-fusion and post-fusion), with significant rearrangements

Glycosylation sites and antigenic regions often lead to low-confidence predictions or register errors in repetitive or shielded areas

AlphaFold models of HA are generally good on the core fold but can struggle with full-length flexibility, glycan masking, and conformational dynamics


These features make HA a strong test case for alternative folding paradigms.

Method: E8 Navigator

The structure was generated using the E8 Navigator, a topology-driven folding engine that projects the amino acid sequence onto the exceptional Lie group E8 lattice based on 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 multiple sequence alignments, neural networks, or patterns memorized from the PDB.

Results

The output PDB (HA_E8_prediction.pdb) converged with Ψ ≈ 2.00 and very low final error (  ERR: ≈0.00009551), producing a compact trimeric-like core with extended flexible regions and no major steric clashes. The model is provided for open inspection and comparison.

Significance

Hemagglutinin is a canonical example of a viral fusion glycoprotein whose structure and dynamics are central to vaccine development and pandemic preparedness. A coherent, clash-free prediction from a purely symmetry-based method — particularly in flexible and glycosylated regions — offers an orthogonal perspective to current AI-driven predictors. This work demonstrates the potential of lattice-based approaches for modeling complex viral surface proteins.

The prediction is shared openly for visualization, alignment against experimental HA structures (e.g. PDB 3LZG, 1HMG), community evaluation, and comparison with other folding methods.

Files included



HA_E8_prediction.pdb — full predicted structure