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Impact of Amidation on Aβ25-35 Aggregation.
Judith C E Etaka1,2, Yan Lu1,2, Wei Kang2
1School of Physics and Optoelectronic Engineering, Hainan University, Haikou 570228, China.
The Journal of Physical Chemistry. B
|February 13, 2025
Summary
Amidation of amyloid-beta (Aβ) peptide fragments affects chain arrangement and secondary structure but not neurotoxicity. Glycine-rich motifs, not overall structure, appear key to Alzheimer's disease peptide toxicity.
Area of Science:
- Neuroscience
- Biochemistry
- Computational Biology
Background:
- Toxic oligomeric species of amyloid-beta (Aβ) peptides are implicated in Alzheimer's disease pathogenesis.
- The Aβ25-35 fragment retains the neurotoxicity of full-length Aβ42 and serves as a model for studying aggregation.
Purpose of the Study:
- To investigate the impact of C-terminal amidation on the aggregation and structural properties of Aβ25-35 trimers using molecular dynamics simulations.
- To determine the relationship between structural changes, fibrillation, and neurotoxicity in amidated versus nonamidated Aβ25-35.
Main Methods:
- Molecular dynamics simulations of Aβ25-35 trimers in both amidated and nonamidated forms.
- Analysis of aggregation pathways, secondary structure content (helix, β-sheet), and inter-chain contacts.
Main Results:
- Amidation of Aβ25-35 resulted in a shift from antiparallel to parallel chain arrangements and increased helical content at the expense of β-sheets.
- Despite structural differences, chain-chain contacts in both amidated and nonamidated systems were primarily mediated by Glycine (GxxxG) motifs and Isoleucine residues.
- Neurotoxicity remained unchanged upon amidation, suggesting it is independent of these observed structural variations.
Conclusions:
- The study implies that the aggregation-promoting Glycine motif is a more significant contributor to Aβ25-35 neurotoxicity than secondary or quaternary structures.
- These findings suggest that targeting specific motifs, rather than overall structural conformations, may be a more effective strategy for mitigating Alzheimer's disease-related peptide toxicity.
