Weaker N-Terminal Interactions for the Protective over the Causative Aβ Peptide Dimer Mutants

Area of Science:

• Neuroscience
• Biochemistry
• Computational Biology

Background:

• Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) peptide aggregation.
• Aβ42 dimers are the smallest and most abundant neurotoxic oligomers implicated in AD pathogenesis.
• Understanding Aβ dimer interactions is crucial for developing AD therapies.

Purpose of the Study:

• To characterize and compare N-terminal interactions of wild-type (WT) and mutant Aβ42 dimers using molecular simulations.
• To investigate the impact of single residue mutations on Aβ dimer stability and conformation.
• To explore the N-terminal hypothesis of AD and potential protective mechanisms.

Main Methods:

• Advanced sampling molecular simulations (replica-exchange) were employed.
• Interactions between N-termini (residues 1-16) of WT-WT and five mutant Aβ42 dimers were analyzed.
• Contact analysis, distance measurements, and contact maps were used to assess conformational landscapes.

Main Results:

• Substantial differences in N-terminal interactions were observed even with single residue changes.
• N-terminal contacts were significantly reduced in protective mutants (e.g., WT-A2T) compared to predisposing mutants (e.g., A2V-A2V) and WT-WT dimers.
• Reduced contacts extended beyond the mutation site, affecting residues up to the 10th position.

Conclusions:

• Findings support the N-terminal hypothesis of Alzheimer's disease.
• Aβ N-terminal interactions play a critical role in dimer stability and neurotoxicity.
• Reduced N-terminal contacts may represent an alternative mechanism for A2T-mediated protection against AD.