Transient interactions between the fuzzy coat and the cross-b core of brain-derived Ab42 filaments
- 1. University of Cambridge, Department of Chemistry
Description
This study investigates the structural properties of amyloid fibrils, prevalent in various human disorders, including Alzheimer's disease. Using the metadynamic electron microscopy metainference (MEMMI) approach, conformational ensembles were generated for two types of amyloid filaments associated with familial and sporadic forms of AD. The results revealed that familial AD filaments exhibit lower solubility compared to sporadic AD filaments, and the fuzzy coat, a disordered region, contributes to increasing the solubility of both filament types. Additionally, analysis of density maps from cryo-EM and MEMMI structural ensembles showed a slowing down of water and sodium ion diffusion near the filament surface, providing insights into the hydration dynamics of amyloid fibrils. This study demonstrates the utility of the metainference approach in analyzing cryo-EM maps for characterizing the properties of amyloid fibrils.
Technical info
The MEMMI method is implemented in the emmi-bias-sigmasem branch of the PLUMED master branch, accessible here (https://github.com/tlhr/plumed2).
The INPUT folder contains the GROMACS topology files, the PLUMED input file, and the associated companion files, including the index file, the GMM data file (map.dat) the structure_renumbered.pdb file, and the production map file used for each Aβ filament type.
The RESULTS directory includes stripped trajectories and structural ensembles for each of the two Aβ filaments.
The ANLAYSIS folder contains the following resources for each filament type: The plumed_files directory, which includes: plumed_analysis.dat, used to print the collective variables (CVs), plumed_reconstruct.dat, used to reconstruct the fibril, plumed_error.dat, used to calculate the error in the GMM data.
A Jupyter notebook generated to perform all analyses
All the files required to run the Jupyter notebook, organized into folders based on the type of analysis.
Files
INPUT.zip
Additional details
Related works
- Is supplement to
- Journal article: 10.1101/2024.01.08.574772 (DOI)
- Journal article: 10.1126/sciadv.adr700 (DOI)