ASM 2019

Talk (C1)


A Molecular Journey to Free Energy Landscapes of Amyloid Forming α-synuclein Fibrils

 

Divya Nayar

Centre for Computational and Data Sciences, IIT Kharagpur

 

ABSTRACT

Neurodegenerative diseases such as Parkinson's disease are known to be caused by the misfolded intrinsically disordered proteins (IDPs) like α-synuclein in the brain [1,2]. It is quite intriguing how these disordered proteins aggregate into highly ordered beta-sheet structures called β-amyloids. The underlying mechanisms of such aggregation are still not well-understood. Molecular dynamics (MD) simulations serve as a useful tool to derive a microscopic understanding of this process. We examine the conformational and binding free energy landscapes of five major fragments of the hydrophobic core of α-synuclein protein, known to be involved in fibrilization [3]. Advanced MD methods such as metadynamics and umbrella sampling are used for molecular investigation. The results quantitatively predict the intrinsic conformational preferences of the protein as well as the crucial interactions between fragments underlying the formation of the fibril. The free energy profiles of the fragments indicate that individual fragments in solution have a preference towards attaining non-β conformations, indicating that in a fibril β-strands are stabilized by interactions with other strands. The results predict that hydrogen bonding stabilizes the collective binding of the five fragments to the end of the fibril, with the hydrophobic interactions adding to further stability. The approach improves the sampling of IDPs and the results provide insights into the binding mechanisms of the fragments to form fibrils in such proteins. The quantitative dissection of the various intermolecular interactions between fragments provide a platform for improving the parameterization of coarse-grained models of such proteins.

 

References

 

1.      Dobson, C. M. Protein misfolding, evolution and disease. Trends Biochem. Sci. 1999, 24, 329−332.

2.      Chiti, F.; Dobson, C. M. Protein Misfolding, Functional Amyloid, and Human Disease. Annu. Rev. Biochem. 2006, 75, 333−366.

3.      Ilie, I. M.; Nayar, D.; den Otter, W. K.; van der Vegt, N. F. A.; Briels, W. J. J. Chem. Theory Comput. 2018, 14, 3298−3310.

 

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