Amyloid beta oligomers: how pH influences over trimer and pentamer structures?

Area of Science:

• Neuroscience
• Biochemistry
• Computational Biology

Background:

• Protein aggregation in the brain is a hallmark of neurodegenerative diseases.
• Alzheimer's disease is characterized by the abnormal aggregation of amyloid-beta 42 (Aβ-42).
• Extrinsic environmental factors, including pH, influence Aβ-42 aggregation.

Purpose of the Study:

• To investigate the effect of pH-induced protonation/deprotonation on Aβ-42 trimeric and pentameric oligomers.
• To analyze the structural stability and conformational changes of Aβ-42 oligomers at different pH values (pH 5, 6, and 7).

Main Methods:

• Utilized molecular dynamics simulations (200 ns) in the canonical ensemble.
• Analyzed the protonation/deprotonation of key residues (histidine, glutamic acid, aspartic acid).
• Employed root mean square deviation (RMSD) analysis to assess structural stability across varying pH conditions.

Main Results:

• Observed significant protonation/deprotonation effects on histidine, glutamic acid, and aspartic acid residues within Aβ-42 oligomers.
• Detected an increase in hydrophobicity of side chains in the trimer at different pHs.
• Found that at pH 5, structural instability in the pentamer led to the exposure of its hydrophobic core.

Conclusions:

• Conformational changes in Aβ-42 oligomers are significantly mediated by pH variations.
• pH-dependent structural alterations are crucial factors in the aggregation process of Aβ-42.
• Understanding these pH-mediated effects provides insights into the mechanisms of Alzheimer's disease pathogenesis.