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Probing the Basis of ?-Synuclein Aggregation by Comparing Simulations to Single-Molecule Experiments.


ABSTRACT: Intrinsically disordered proteins often play an important role in protein aggregation. However, it is challenging to determine the structures and interactions that drive the early stages of aggregation because they are transient and obscured in a heterogeneous mixture of disordered states. Even computational methods are limited because the lack of ordered structure makes it difficult to ensure that the relevant conformations are sampled. We address these challenges by integrating atomistic simulations with high-resolution single-molecule measurements reported previously, using the measurements to help discern which parts of the disordered ensemble of structures in the simulations are most probable while using the simulations to identify residues and interactions that are important for oligomer stability. This approach was applied to ?-synuclein, an intrinsically disordered protein that aggregates in the context of Parkinson's disease. We simulated single-molecule pulling experiments on dimers, the minimal oligomer, and compared them to force spectroscopy measurements. Force-extension curves were simulated starting from a set of 66 structures with substantial structured content selected from the ensemble of dimer structures generated at zero force via Monte Carlo simulations. The pattern of contour length changes as the structures unfolded through intermediate states was compared to the results from optical trapping measurements on the same dimer to discern likely structures occurring in the measurements. Simulated pulling curves were generally consistent with experimental data but with a larger number of transient intermediates. We identified an ensemble of ?-rich dimer structures consistent with the experimental data from which dimer interfaces could be deduced. These results suggest specific druggable targets in the structural motifs of ?-synuclein that may help prevent the earliest steps of oligomerization.

SUBMITTER: Churchill CDM 

PROVIDER: S-EPMC6818160 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

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