Session X39: Focus Session: Crystal Growth of and Moderated by Proteins

2:30 PM–5:30 PM, Thursday, March 19, 2009
Room: 411

Sponsoring Unit: DBP
Chair: Raymond Friddle, Lawrence Livermore National Laboratory

Abstract ID: BAPS.2009.MAR.X39.9

Abstract: X39.00009 : Atomistic Investigation of Cu-Induced Misfolding in the Onset of Parkinson's Disease

4:54 PM–5:06 PM

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  Francis Rose

  Miroslav Hodak

  Jerry Bernholc

A nucleation mechanism for the misfolding of $\alpha$-synuclein, the protein implicated in Parkinson's Disease (PD), is investigated using computer simulations. Through a combination of ab initio and classical simulation techniques, the conformational evolution of copper-ion-initiated misfolding of $\alpha$-synuclein is determined. Based on these investigations and available experimental evidence, an atomistic model detailing the nucleation-initiated pathogenesis of PD is proposed. Once misfolded, the proteins can assemble into fibrils, the primary structural components of the deleterious PD plaques. Our model identifies a process of structural modifications to an initially unfolded $\alpha$-synuclein that results in a partially folded intermediate with a well defined nucleation site as a precursor to the fully misfolded protein. The identified pathway can enable studies of reversal mechanisms and inhibitory agents, potentially leading to the development of effective therapies.

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