Characterization of Phosphorylated Tau-Microtubule complex with Molecular Dynamics (MD) simulation

TL;DR

This study uses molecular dynamics simulations to explore how pseudo-phosphorylation affects tau protein conformations within the tau-microtubule complex, providing insights into mechanisms linked to Alzheimer's disease.

Contribution

It introduces a detailed MD simulation approach to analyze pseudo-phosphorylated tau-microtubule interactions, revealing conformational changes and key residues involved.

Findings

Pseudo-phosphorylation alters tau conformations.

Key residues responsible for conformational shifts identified.

Enhanced understanding of tau aggregation mechanisms in AD.

Abstract

Alzheimer's Disease (AD), a neurodegenerative disorder, is reported as one of the most severe health and socioeconomic problems in current public health. Tau proteins are assumed to be a crucial driving factor of AD that detach from microtubules (MT) and accumulate as neurotoxic aggregates in the brains of AD patients. Extensive experimental and computational research has observed that phosphorylation at specific tau residues enhances aggregation, but the exact mechanisms underlying this phenomenon remain unclear. In this study, we employed molecular dynamics (MD) simulations on pseudo-phosphorylated tau-MT complex (residue 199 ~ 312), incorporating structural data from recent cryo-electron microscopy studies. Simulation results have revealed altered tau conformations after applying pseudo-phosphorylation. Additionally, root-mean-square deviation (RMSD) analyses and dimensionality reduction of dihedral angles revealed key residues responsible for these conformational shifts