Aggregation Mechanism of Alzheimer’s Amyloid β-Peptide Mediated by α-Strand/α-Sheet Structure

Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and a widespread form of dementia. Aggregated forms of the amyloid β-peptide (Aβ) are identified as a toxic species responsible for neuronal damage in AD. Extensive research has been conducted to reveal the aggregation mechanism of Aβ. However, the structure of pathological aggregates and the mechanism of aggregation are not well understood. Recently, experimental studies have confirmed that the α-sheet structure in Aβ drives aggregation and toxicity in AD. However, how the α-sheet structure is formed in Aβ and how it contributes to Aβ aggregation remains elusive. In the present study, molecular dynamics simulations suggest that Aβ adopts the α-strand conformation by peptide-plane flipping. Multiple α-strands interact through hydrogen bonding to form α-sheets. This structure acts as a nucleus that initiates and promotes aggregation and fibrillation of Aβ. Our findings are supported by previous experimental as well as theoretical studies. This study provides valuable structural insights for the design of anti-AD drugs exploiting the α-strand/α-sheet structure.

The role of α-sheet structure in amyloidogenesis: characterization and implications

“…Until its independent 'rediscovery' in the Daggett lab, the structure was dismissed and considered to be a rare and alternative conformation to the energetically favourable β-sheet, which is correct for normal, native proteins. Following its observation in MD simulations conducted by the Daggett lab, α-sheet structure has been observed in a number of other MD simulations of amyloid proteins [51][52][53][54][55][56].…”

“…Next, we sought to further validate the presence of α-sheet structure in our de novo peptides through MMS-IR, which reports on amide I band absorption (1714 cm −1 to 1590 cm −1 ) [ 52 ]. Amide I band absorption is correlated with shifts in hydrogen bonding patterns and dipole–dipole interactions, and can therefore aid in determining protein secondary structure [ 77 ].…”

“…α-Sheet structure is stabilized by hydrogen bonding between individual α-strands, similar to the formation of standard β-sheet secondary structure [32,33,51,52,57,58]. Amino acids that form the strands are locally helical, occupying the left- ( α L ) and right-handed ( α R ) helical regions of Ramachandran space (figure 2 a ) [32,57–59].…”

“…Amino acids that form the strands are locally helical, occupying the left-(α L ) and right-handed (α R ) helical regions of Ramachandran space (figure 2a) [32,[57][58][59]. Sequential alternation between α L and α R backbone (Φ, Ψ) dihedral angles results in the formation of an elongated strand (figure 2b) [32,52,57,59]. Sheets are formed with bifurcated hydrogen bonding between individual residues in adjacent strands (figure 2c) [32,57,60].…”

Tumorigenic p53 mutants undergo common structural disruptions including conversion to α‐sheet structure

“…In addition, α-sheet formation is not unique to our simulation methods or force field. Other investigators have also observed α-sheet in silico using other simulation packages and other force fields, including TTR (AMBER program, parm94 force field), 68 α-synuclein (GROMACS, CHARMM27), 69,70 β-amyloid peptide (GROMACS, CHARMM36m), polyglutamine (GROMOS, GROMOS96), 71 and others. [72][73][74][75][76] By way of comparison, we point out that we do not observe α-sheet formation in "normal" proteins.…”