Amyloid β-peptide (Aβ1-42) is known to be the primary component of
the amyloid plaques found in the brain of patients suffering from Alzheimer’s disease
(AD). Extensive research has been done in the past with respect to Aβ1-42 peptide
and its involvement in AD. However, the initial seed structure responsible for
the Aβ1-42 peptide aggregation and the mechanism remains unclear. This may be
chiefly attributed to the poor understanding of the processes involved in the Aβ1-42
peptide mis-folding and aggregation. Further, the flexibility and the aggregation
propensity involved in the Aβ1-42 monomer, challenges the experimental and theoretical
techniques to characterize the seed structure that drives the mis-folding and
the subsequent aberrant aggregation. In this study, we employed all atoms fully
unrestrained folding molecular dynamics simulation to identify the probable seed
structure of Aβ1-42 peptide responsible for the aggregation. The initial linear structure of the Aβ1-42
peptide for the simulation was built from its amino acid sequence using leap module of AMBER.
From our molecular dynamics study, we followed the secondary structure development in Aβ1-42
peptide starting from its initial linear structure to its folded 3D structure. We observed the Aβ1-42
peptide to sample diverse conformations which are rich in β-sheets and are stabilized by hydrogen
bonding and other non-bonding interactions. The findings of this study shall be helpful in understanding
the initial stage of Aβ1-42 peptide aggregation process and can be applicable for the development
of therapeutics to cure AD at an early stage.
Keywords: Alzheimer's, AMBER, misfolding, protein aggregation.
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