Conformational ensemble of native -synuclein in solution as determined by short-distance crosslinking constraint-guided discrete molecular dynamics simulations

Combining structural proteomics experimental data with computational methods is a powerful tool for protein structure prediction. Here, we apply a recently-developed approach for de novo protein structure determination based on the incorporation of short-distance crosslinking data as constraints in discrete molecular dynamics simulations (CL-DMD) for the determination of conformational ensemble of the intrinsically disordered protein -synuclein in the solution. The predicted structures were in agreement with hydrogen-deuterium exchange, circular dichroism, surface modification, and long-distance crosslinking data. We found that -synuclein is present in solution as an ensemble of rather compact globular conformations with distinct topology and inter-residue contacts, which is well-represented by movements of the large loops and formation of few transient secondary structure elements. Non-amyloid component and C-terminal regions were consistently found to contain -structure elements and hairpins. Author summary As the population ages, neurodegenerative diseases such as Parkinson's disease will become an increasing problem in many countries. Aggregation of the protein -synuclein is the primary cause of Parkinson's disease, but there is still a dearth of structural information pertaining to the native, non-aggregating form of this protein. A better understanding the structural state of the native protein may prove useful for the design of new therapeutics to combat this disease. In order to obtain more structural information on this protein, we have recently modelled the native -synuclein protein. These models were generated using a novel approach which combines protein crosslinking and discrete molecular dynamics simulations. We have found that the -synuclein protein can adopt several shapes, all with a similar topology, resembling a three fingered closed claw. A region of the protein important for aggregation was found to be protected from the surrounding biological environment in these conformations, and the stabilization of these structures may be a fruitful avenue for future drug research into mitigating the cause and effect of Parkinson's disease.