Structures of the amyloid β-peptides Aβ1-40 and Aβ1-42 as influenced by pH and a D-peptide

Area of Science:

• Biochemistry
• Computational Biology
• Neuroscience

Background:

• Alzheimer's disease (AD) is characterized by the aggregation of amyloid peptides, primarily Aβ(1-40) and Aβ(1-42).
• Understanding the secondary structure and conformational dynamics of these peptides is crucial for developing therapeutic strategies.
• Molecular dynamics (MD) simulations offer a powerful tool to investigate peptide behavior at the atomic level.

Purpose of the Study:

• To compare the secondary structure of Aβ(1-40) and Aβ(1-42) using microsecond-scale MD simulations.
• To evaluate the performance of two GROMOS96 force fields (ffG43a2 and ffG53a6) in modeling these peptides.
• To investigate the structural effects of pH and the binding of the antiamyloid peptide D3 on Aβ(1-42).

Main Methods:

• Microsecond-scale molecular dynamics (MD) simulations of Aβ(1-40) and Aβ(1-42) using GROMOS96 force fields ffG43a2 and ffG53a6.
• Calculation and validation of NMR chemical shifts against experimental data to characterize sampled conformations.
• Simulation of Aβ(1-42) under varying pH conditions and in complex with the D3 peptide.

Main Results:

• Significant peptide and force field-dependent differences were observed in the conformations of Aβ(1-40) and Aβ(1-42).
• The ffG53a6 force field demonstrated superior ability in modeling the structural propensities of both Aβ(1-40) and Aβ(1-42) compared to ffG43a2.
• Under acidic conditions, histidine protonation in Aβ(1-42) promoted β-sheet formation.
• Binding of D3 to Aβ(1-42) was driven by electrostatic interactions and resulted in a significant reduction of β-sheet structures, potentially explaining its amyloid-inhibiting properties.

Conclusions:

• The ffG53a6 force field is recommended for future simulations of Aβ(1-40) and Aβ(1-42).
• pH influences Aβ(1-42) secondary structure through histidine protonation.
• The D3 peptide inhibits amyloid formation by disrupting Aβ(1-42) β-sheet structures via electrostatic interactions.