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ACS Chem Neurosci. 2017 Apr 19;8(4):837-849. doi: 10.1021/acschemneuro.6b00406. Epub 2017 Jan 27.

Familial Mutations May Switch Conformational Preferences in α-Synuclein Fibrils.

Author information

1
Department of Physics, Bernal Institute, University of Limerick , Limerick, Ireland.
2
Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, National Cancer Institute , Frederick, Maryland 21702, United States.
3
Sackler Inst. of Molecular Medicine Department of Human Genetics and Molecular Medicine Sackler School of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.

Abstract

The pathogenesis of Parkinson's disease is closely associated with the aggregation of the α-synuclein protein. Several familial mutants have been identified and shown to affect the aggregation kinetics of α-synuclein through distinct molecular mechanisms. Quantitative evaluation of the relative stabilities of the wild type and mutant fibrils is crucial for understanding the aggregation process and identifying the key component steps. In this work, we examined two topologically different α-synuclein fibril structures that are either determined by solid-state NMR method or modeled based on solid-state NMR data, and characterized their conformational properties and thermodynamic stabilities using molecular dynamics simulations. We show that the two fibril morphologies have comparable size, solvent exposure, secondary structures, and similar molecule/peptide binding modes; but different stabilities. Familial mutations do not significantly alter the overall fibril structures but shift their relative stabilities. Distinct mutations display altered fibril conformational behavior, suggesting different propagation preferences, reminiscent of cross-seeding among prion strains and tau deletion mutants. The simulations quantify the hydrophobic and electrostatic interactions, as well as N-terminal dynamics, that may contribute to the divergent aggregation kinetics that has been observed experimentally. Our results indicate that small molecule and peptide inhibitors may share the same binding region, providing molecular recognition that is independent of fibril conformation.

KEYWORDS:

Parkinson’s disease; amyloid aggregation; molecular dynamics simulations; mutation; α-Synuclein

PMID:
28075555
DOI:
10.1021/acschemneuro.6b00406
[Indexed for MEDLINE]

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