Dimer formation enhances structural differences between amyloid β-protein (1-40) and (1-42): an explicit-solvent...

Area of Science:

• Biochemistry
• Computational Biology
• Neuroscience

Background:

• Amyloid β-protein (Aβ) aggregation is central to Alzheimer's disease (AD) pathology.
• The two main alloforms, Aβ(1-40) and Aβ(1-42), exhibit distinct assembly and toxicity due to a 5% structural difference.

Purpose of the Study:

• To investigate the molecular dynamics and conformational differences between Aβ(1-40) and Aβ(1-42) dimers.
• To explore the role of charged amino acids in Aβ alloform assembly and potential toxicity.

Main Methods:

• Utilized Discrete Molecular Dynamics (DMD) for initial studies.
• Employed fully atomistic Molecular Dynamics (MD) simulations with OPLS-AA force field and SPCE/TIP3P water models.
• Analyzed free energy landscapes, conformational variability, and salt bridge formation.

Main Results:

• Atomistic simulations showed larger, less compact conformations than DMD predictions.
• Aβ(1-42) dimers exhibited greater conformational variability and N-terminal flexibility than Aβ(1-40) dimers.
• Salt bridge formation increased with dimerization, with notable differences in K28 propensity between alloforms.

Conclusions:

• Aβ(1-42) dimers display increased flexibility and solvent exposure of charged residues compared to Aβ(1-40).
• Specific charged amino acid interactions (e.g., R5, K28) differ between alloforms and may influence oligomer toxicity.
• Findings provide molecular insights into alloform-specific Aβ assembly relevant to Alzheimer's disease pathogenesis.