Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue
Data files
Mar 06, 2024 version files 12.99 GB
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0to200ns_traj.dcd
12.88 GB
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ionized.pdb
24.21 MB
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ionized.psf
35.87 MB
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pdb_first_and_last.pdb
48.42 MB
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README.md
3.71 KB
Abstract
The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. We developed and validated a novel method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and used solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and enable new approaches for studies of disease mechanisms, imaging agents and therapeutics targeting Asyn.
README: Structure of Alpha-Synuclein Fibrils Derived from Human Lewy Body Dementia Tissue
https://doi.org/10.5061/dryad.tx95x6b4z
Description of the data and file structure
Dryad
File 1: 0to200ns_traj.dcd
An all-atom MD simulation of a two-fold symmetric Asyn fibril (2x20-mer) was performed using NAMD 3.0. The CHARMM36m protein force field was applied to the fibrils. We simulated the fibril in an explicit water box of size 180 x 100 x 180 Å3 with an ion concentration of 0.15 M (NaCl solution) using an NPT ensemble with N = 306450, P = 1.01325 bar and T = 310 K. The system was subjected to Langevin dynamics with damping constant γ = 1.0 ps^-1 and the Nosé-Hoover Langevin piston method was employed to maintain constant pressure. The MD integration time step was set to 2 fs. To evaluate long range electrostatic interactions, particle mesh Ewald was used in the presence of periodic boundary conditions. Non-bonded van der Waals (vdW) interactions were calculated with the Lennard-Jones potential with a cutoff distance of 12 Å. A smoothing function was introduced at 10 Å to gradually truncate the vdW potential energy at the cut-off distance. 14 Å cutoff distance was used to identify the atom pairs for vdW interaction. The system was first energetically minimized for 1000 steps by conjugate gradient method followed by a 10 ns equilibration of water and ions in the presence of positional restraints (force constant: 1 kcal/mol Å2) on Cα atoms of the fibril. The system was then simulated for 200 ns without any restraints. Simulation trajectories were collected every 50 ps.
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File 2: ionized.pdb
Initial ionized .pdb file
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File 3: ionized.psf
Initial .psf file for NAMD simulation
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File 4: pdb_first_and_last.pdb
.pdb file of the initial and the final structure from the 0to200ns_traj.dcd 200 ns simulation.
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Zenodo
File 5: mean_and_std.ipynb
iPython notebook containing scripts to generate figures of the mean and standard deviation of each residue through the time course of the MD simulation
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File 6: Calc_grid_density.ipynb
iPython notebook containing scripts to calculate and generate figures measuring the density of ions
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File 7: Calc_align_and_RMSF_2.ipynb
iPython notebook containing scripts to calculate and generate figures to calculate the root mean squared fluctuations of each residue through the time course of the MD simulation.
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File 8: Calc_RMSD.ipynb
iPython notebook containing scripts to calculate and generate figures measuring the region-wise RMSD deviation over the time course of the MD simulation
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Code/Software
Analysis was performed with VMD and in-house python scripts leveraging the Numpy, Scipy, Pandas, and MDanalysis scientific computing packages. Figures were made for the corresponding publication using matplotlib and chimeraX with standard configurations.
To open and view the provided simulation files, VMD (freely downloadable at https://www.ks.uiuc.edu/Research/vmd/ ) may be used to load the simulation when opened the .dcd and the .psf are opened together. VMD is also capable of opening the .pdb files provided. ChimeraX is also capable of opening the .dcd, .psf and .pdb files and viewing their contents.