DOI: 10.5281/zenodo.18489374
title: Long isoform of human microtubule-associated protein tau (MAPT) prediction via E8 lattice topological optimization

description: Protein target

This record contains the predicted 3D structure of a long isoform of human microtubule-associated protein tau (MAPT / tau protein, UniProt A0A7I2PJZ2, 833 amino acids), generated using the E8 Navigator — a symmetry-based, non-data-driven protein folding method.MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEAEEAGIGDTPSLEDEAAGHVTQEELRVPGRQRKAPERPLANEISAHVQPGPCGEASGVSGPCLGEKEPEAPVPLTASLPQHRPVCPAPPPTGGPQEPSLEWGQKGGDWAEKGPAFPKPATTAYLHTEPESGKVVQEGFLREPGPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEGGRHAPELLKHQLLGDLHQEGPPLKGAGGKERPGSKEEVDEDRDVDESSPQDSPPSKASPAQDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKVSTEIPASEPDGPSVGRAKGQDAPLEFTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEADLPEPSEKQPAAAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPCLSPKHPTPGSSDPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL

Biological relevance

Tau is a microtubule-associated protein critical for neuronal microtubule stability, axonal transport, and cytoskeletal organization. It is central to a group of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (where hyperphosphorylated tau forms neurofibrillary tangles), frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration. Understanding tau's structural ensemble and conformational dynamics is essential for elucidating aggregation mechanisms and developing therapeutics.

Why this is a challenging folding problem

Tau is intrinsically disordered and structurally difficult for conventional prediction methods:



Approximately 90% of the protein is intrinsically disordered, with only short, transient secondary structure elements in microtubule-binding repeat regions

The longest isoforms (including this one) contain extended unstructured regions and multiple repeat domains that are prone to collapse or low-confidence predictions

No high-resolution experimental structure exists for full-length tau due to its extreme flexibility and disorder

AlphaFold and similar tools typically assign very low pLDDT scores (<50) across most of the sequence, especially in the long disordered regions and repeat domains


These characteristics make tau a canonical test case for methods that aim to model disordered or flexible proteins.

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 treated 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 (A0A7I2PJZ2_E8_prediction.pdb) converged with Ψ = 2.00 and very low final error (ERR: 0.00012640), yielding a structured core (likely corresponding to microtubule-binding repeats) surrounded by extended, flexible regions consistent with tau's intrinsically disordered nature. No major steric clashes were observed.

Significance

Tau is a paradigm example of an intrinsically disordered protein whose pathological aggregation drives major neurodegenerative diseases. A coherent prediction from a purely symmetry-based method — particularly in disordered and repeat-containing regions — provides an orthogonal perspective to current AI-driven predictors. This is highly relevant for understanding tau conformational ensembles, aggregation propensity, and potential therapeutic targeting.

The prediction is shared openly for visualization, alignment against experimental tau fragments (e.g. PDB 5O3L, 6MZ9), community evaluation, and comparison with other folding approaches.

Files included



A0A7I2PJZ2_E8_prediction.pdb — full predicted structure