Computational study of conformational interconversion of an amyloid β double layer system

Area of Science:

• Biochemistry
• Computational Chemistry
• Neuroscience

Background:

• Alzheimer's disease (AD) is linked to amyloid β (Aβ) peptide fibril formation.
• Understanding Aβ peptide structural dynamics is crucial for AD research.

Purpose of the Study:

• To theoretically investigate conformational changes in double-layer Aβ^20-34 peptide structures.
• To analyze the energy landscape and transition barriers between flat and twisted conformations.

Main Methods:

• Density Functional Theory (DFT) calculations were employed.
• The nudged elastic band (NEB) method was used to map the potential energy surface.
• Structural analysis identified key interactions and steric factors.

Main Results:

• Several twisted conformations of Aβ^20-34 were identified as local energy minima.
• The transition from flat to twisted conformations is endothermic, driven by broken hydrogen bonds and lost van der Waals interactions.
• Activation barriers varied, with some twisted conformations readily reverting to flat, while others were more stable.

Conclusions:

• Aβ^20-34 peptides can adopt stable twisted conformations.
• The stability and reversibility of these conformations depend on specific sidechain interactions and steric hindrance.
• These findings provide insights into the early stages of amyloid fibril formation in Alzheimer's disease.