Oligomeric Structures of an Aggregation-Triggering Fragment of SOD1 Protein

Abstract

Abstract: Amyloid fibril formation of copper-zinc superoxide dismutase (SOD1) is linked to familial amyotrophic lateral sclerosis (fALS), a progressive neurodegenerative disease. A recent experimental study has shown that 147GVIGIAQ153 peptide of the SOD1 C-terminal segment can form amyloid fibril and also accelerate the aggregation of full-length SOD1, while substitution of isoleucine at site 149 by proline blocks fibril formation of this peptide. However, the oligomeric structure and aggregation mechanism of this fragment remain elusive. In this study, we have investigated the hexameric structures of GVIGIAQ and its I149P variant by performing extensive atomistic explicit-solvent replica exchange molecular dynamics (REMD) simulations. We found that the GVIGIAQ hexamers adopt various β-sheet-rich conformations, including disordered aggregates and, to a much lesser extent, ordered fibril-like bilayer β-sheets and β-barrels. Structural analysis shows that four-stranded monolayer β-sheets are the smallest β-sheets that can form both bilayer β-sheets and β-barrels. In contrast, substitution of I149 by proline significantly reduces the β-sheet probability of all residues, especially those close to I149 in amino acid sequence, thus resulting in the vanish of bilayer β-sheets, a decrease of β-barrels, and a dramatic increase of disordered aggregates. The lack of bilayer β-sheets provides an explanation for the experimental observation of no fibril formation for I149P variant. MD simulation results on the structural stability of different sizes of experimental bilayer β-sheet fibril models further support the importance of I149 on fibril formation and also suggest that the bilayer β-sheet consisting of eight chains might be the smallest nucleus for 147GVIGIAQ153 fibril formation.