(334bi) Determining the Folding Landscape of ?-Synuclein (35-97) Using Replica Exchange Molecular Dynamics

Synucleinopathies are a group of neurodegenerative disorders such as Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy-bodies (DLB) that affects millions of people worldwide. They are characterized by abnormal aggregation or fibrillation of a-synuclein protein inside the nerve fibers or glial cells. These disorders are clinically characterized by memory and cognitive impairment, decline in motor or autonomic functions. α-synuclein is an intrinsically disordered protein which under pathological conditions undergoes structured transformation to oligomers containing β-pleated sheets that assists in its fibrillation process. The central amino acids from 35 to 97 (63 residues) play a major role in fibril formation and take up a unique Greek-key topology. The characterization of conformations accessible to monomeric α-synuclein is crucial in understanding the pathway to fibrillation. In this study, we use replica-exchange molecular dynamics methods to determine the folding landscape of α-synuclein fragment (35 – 97). We are able to obtain microscopic level information and thus, gain better understanding of protein folding by using an all-atom peptide model. The results provided also include the effect of temperature on these properties and the secondary structure analysis.