DOI: 10.5281/zenodo.18484025
title: p53 (full-length human tumor protein 53) predicted structure via E8 lattice topological optimization

description: Protein target

This record presents the predicted 3D structure of full-length human p53 (UniProt P04637, 393 amino acids), generated using the E8 Navigator — a non-data-driven, symmetry-based protein folding method.MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD

Biological relevance

p53 is one of the most important tumor suppressor proteins in human biology, often called “the guardian of the genome”. It is mutated in approximately 50% of all human cancers and plays a central role in DNA damage response, cell-cycle arrest, apoptosis, and senescence. The protein is heavily involved in lung cancer, breast cancer, colorectal cancer, and many others. Its function relies on a highly dynamic, intrinsically disordered architecture that allows it to interact with hundreds of partners in a context-dependent manner.

Why this is a challenging folding problem

p53 is notoriously difficult for conventional structure prediction methods:



Approximately 50–60% of the protein consists of intrinsically disordered regions (IDRs), particularly the N-terminal transactivation domain and the C-terminal regulatory domain

The central DNA-binding domain (residues ~94–292) is well-structured, but the flanking disordered tails mediate critical interactions and are prone to collapse or low-confidence predictions

p53 exists in multiple conformational ensembles; pathogenic mutations (e.g., R175H, R248Q, R273H) alter dynamics and stability in subtle ways

AlphaFold and similar tools typically assign low pLDDT scores to the disordered regions and struggle to capture functional flexibility without additional context


Method: E8 Navigator

The structure was produced 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 a symmetry-constrained optimization problem on the E8 manifold, guided by a holographic coherence metric (Ψ) and convergence to ultra-low error states — without using multiple sequence alignments, neural networks, or patterns memorized from the PDB.

Results

The output PDB (p53_E8_prediction.pdb) converged with Ψ ≈ 2.00 and very low final error ERR  ≈  0.00007606, yielding a structured DNA-binding domain core surrounded by extended, flexible N- and C-terminal regions consistent with its intrinsically disordered character. No major steric clashes were observed in the final model.

Significance

p53 represents a canonical example of an intrinsically disordered protein whose function emerges from structural flexibility rather than a single fixed fold. A clean, coherent prediction from a purely symmetry-based method — especially in the disordered regions — offers an orthogonal perspective to current AI-driven predictors. This is particularly relevant for understanding p53-related cancers, where mutations often act through changes in conformational dynamics.

The prediction is shared openly for visualization, alignment against experimental domain structures (e.g., DNA-binding domain PDB 1TUP, 2OCJ), community evaluation, and comparison with other folding approaches.

Files included



p53_E8_prediction.pdb — full predicted structure