Investigations on the Structural Characteristics that Seed the Aggregation of Amyloid-β_1-42 Peptide: Insights from Molecular Dynamics Simulations

Title:Investigations on the Structural Characteristics that Seed the Aggregation of Amyloid-β_1-42 Peptide: Insights from Molecular Dynamics Simulations

Volume: 13 Issue: 3

Author(s): Mary Dutta, Ankita Deb and Mattaparthi Venkata Satish Kumar

Affiliation:

Keywords: Alzheimer's, AMBER, misfolding, protein aggregation.

Abstract: Amyloid β-peptide (Aβ_1-42) 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 Aβ_1-42 peptide and its involvement in AD. However, the initial seed structure responsible for the Aβ_1-42 peptide aggregation and the mechanism remains unclear. This may be chiefly attributed to the poor understanding of the processes involved in the Aβ_1-42 peptide mis-folding and aggregation. Further, the flexibility and the aggregation propensity involved in the Aβ_1-42 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 Aβ_1-42 peptide responsible for the aggregation. The initial linear structure of the Aβ_1-42 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 Aβ_1-42 peptide starting from its initial linear structure to its folded 3D structure. We observed the Aβ_1-42 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 Aβ_1-42 peptide aggregation process and can be applicable for the development of therapeutics to cure AD at an early stage.

Cite this article as:

Dutta Mary, Deb Ankita and Kumar Venkata Satish Mattaparthi, Investigations on the Structural Characteristics that Seed the Aggregation of Amyloid-β_1-42 Peptide: Insights from Molecular Dynamics Simulations, Current Proteomics 2016; 13 (3) . https://dx.doi.org/10.2174/1570164613999160831110617