title: Critical Nucleus Structure and Aggregation Mechanism of the C-terminal Fragment of Copper-Zinc Superoxide Dismutase Protein.
abstract: The aggregation of the copper-zinc superoxide dismutase (SOD1) protein is linked to familial amyotrophic lateral sclerosis, a progressive neurodegenerative disease. A recent experimental study has shown that the (147)GVIGIAQ(153) SOD1 C-terminal segment not only forms amyloid fibrils in isolation but also accelerates the aggregation of full-length SOD1, while substitution of isoleucine at site 149 by proline blocks its fibril formation. Amyloid formation is a nucleation-polymerization process. In this study, we investigated the oligomerization and the nucleus structure of this heptapeptide. By performing extensive replica-exchange molecular dynamics (REMD) simulations and conventional MD simulations, we found that the GVIGIAQ hexamers can adopt highly ordered bilayer β-sheets and β-barrels. In contrast, substitution of I149 by proline significantly reduces the β-sheet probability and results in the disappearance of bilayer β-sheet structures and the increase of disordered hexamers. We identified mixed parallel-antiparallel bilayer β-sheets in both REMD and conventional MD simulations and provided the conformational transition from the experimentally observed parallel bilayer sheets to the mixed parallel-antiparallel bilayer β-sheets. Our simulations suggest that the critical nucleus consists of six peptide chains and two additional peptide chains strongly stabilize this critical nucleus. The stabilized octamer is able to recruit additional random peptides into the β-sheet. Therefore, our simulations provide insights into the critical nucleus formation and the smallest stable nucleus of the (147)GVIGIAQ(153) peptide.
authors.affiliation: College of Physical Education and Training, Shanghai University of Sport , 399 Chang Hai Road, Shanghai 200438, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Physics, Fudan University , 220 Handan Road, Shanghai 200433, China.
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: College of Physical Education and Training, Shanghai University of Sport , 399 Chang Hai Road, Shanghai 200438, China.
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute , Frederick, Maryland 21702, United States.
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute , Frederick, Maryland 21702, United States.|Sackler Inst. of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: College of Physical Education and Training, Shanghai University of Sport , 399 Chang Hai Road, Shanghai 200438, China.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D000072757:Protein Conformation, beta-Strand; D000072105:Superoxide Dismutase-1 / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D010455:Peptides; D000072105:Superoxide Dismutase-1
keywords: Replica exchange method; bilayer β-sheet; free energy landscape; molecular dynamics simulations; nucleus; oligomers
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