Entry PED1AAD: Beta-synuclein: solution-state ensemble from PRE-NMR ensemble-restrained MD simulations

Entry summary

Random pool MD SAXS NMR Validated

Authors: Jane R. Allison; Robert Rivers; John C. Christodoulou; Michele Vendruscolo; Christopher M. Dobson

Publication: A relationship between the transient structure in the monomeric state and the aggregation propensities of alpha-synuclein and beta-synuclein

Release date: 0000-00-00


Ensemble of structures corresponding to the intrinsically disordered solution state of beta-synuclein generated using ensemble-restrained molecular dynamics simulations restrained with inter-atomic distances derived from paramagnetic relaxation enhancement NMR.

Calculation procedure:

Seven different cysteine mutations of beta-synuclein were created. The protein was over-expressed in E. coli and purified. An MTSL spin label was attached to the inserted cysteine residue. Paramagnetic relaxation enhancement NMR with the spin label in its reduced and oxidised state was carried out. The ratio of the peak intensities in each state (Iox/Ired) was used to derive distances between spin label and amide protons. The distances were filtered to remove those with high uncertainty (shortest and longest, 17% of total number of distances), giving 635 distances that were further divided into a working (508) and free (127) datasets, with only the working set used to calculate the ensemble of structures. The working distances were used as distance restraints (with the distance defined as being between the Calpha atom of the spin-labelled residue, which retains its native identity, and the amide proton of other residues) in ensemble-restrained molecular dynamics simulations. The CHARMM software (with in-house modifications to allow ensemble-averaging) was used with the SASA implicit solvation model with default cut-off distances for non-bonded and electrostatic interactions and rectangular periodic boundary conditions. The ^{-6}-averaged distances (average calculated over 24 independent replicas simulated in parallel) were compared to experimental value at each time point. A flat-bottom harmonic restraint potential, where distances within 1 Angstrom less than target distance or 8 Angstroms above target distance are not penalised, was used. The simulation temperature (525 K) was chosen according to best agreement between ensemble-averaged Rh (^{-1}) and experimental value. Structures were collected every 5 ps for 1.2 ns per replica, giving 5760 structures in total. Every 10th structure is provided here.

Sample images

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Most compact conformation

Average conformation

Most extended conformation

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Protein information


Biological function: Non-amyloid component of senile plaques found in Alzheimer disease. Could act as a regulator of SNCA aggregation process. Protects neurons from staurosporine and 6-hydroxy dopamine (6OHDA)-stimulated caspase activation in a p53/TP53-dependent manner. Contributes to restore the SNCA anti-apoptotic function abolished by 6OHDA. Not found in the Lewy bodies associated with Parkinson disease. [ref]

Protein name: beta-synuclein
UniProt link: Q16143
Organism: Homo sapiens
Expressed in: E.coli
Number of residues: 134
Theoretic molecular weight: 14287.8
Theoretic isoelectric point: 4.41
Sequence range (relative to UniProt):
Post-translational modifications: None
Mutations: None

Amino acid sequence:


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NMR information

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Data not deposited in BMRB

NMR Experimental set #1