All-atom Molecular Dynamics Simulations of the Projection Domain of the Intrinsically Disordered htau40 Protein

TL;DR

This study uses all-atom molecular dynamics simulations to explore the conformational behavior of the projection domain of the intrinsically disordered htau40 protein, comparing simulation results with experimental data and analyzing structural ensembles.

Contribution

It introduces a comprehensive simulation approach for the tau protein domain, validating force fields and initial conditions, and identifies distinct conformational groups.

Findings

Chemical shift spectrum aligns more with filamentous tau.

Identified three main conformational groups: globules, tadpoles, extended structures.

Results are robust across different force fields and water models.

Abstract

We have performed all atom molecular dynamics simulations on the projection domain of the intrinsically disordered htau40 protein. After generating a suitable ensemble of starting conformations at high temperatures, at room temperature in an adaptive box algorithm we have generated histograms for the radius of gyration, secondary structure time series, generated model small angle x-ray scattering intensities, and model chemical shift plots for comparison to nuclear magnetic resonance data for solvated and filamentous tau. Significantly, we find that the chemical shift spectrum is more consistent with filamentous tau than full length solution based tau. We have also carried out principle component analysis and find three basics groups: compact globules, tadpoles, and extended hinging structures. To validate the adaptive box and our force field choice, we have run limited simulations in a large conventional box with varying force fields and find that our essential results are unchanged. We also performed two simulations with the TIP4P-D water model, the effects of which depended on whether the initial configuration was compact or extended.