Metal Binding to Amyloid-β_1-42: A Ligand Field Molecular Dynamics Study

Area of Science:

• Biophysics
• Computational Chemistry
• Neuroscience

Background:

• Amyloid-beta (Aβ) peptide aggregation into fibrils is implicated in Alzheimer's disease.
• Metal ions, including copper and platinum, are found in amyloid plaques and can influence Aβ aggregation.
• Understanding metal-Aβ interactions is crucial for developing therapeutic strategies.

Purpose of the Study:

• To investigate the structural impact of copper(II) and platinum(II) binding on the amyloid-beta (Aβ)_1-42 peptide monomer.
• To compare the molecular dynamics of metal-bound Aβ peptides with the free Aβ monomer.
• To elucidate how metal binding affects secondary structure, overall conformation, and key salt bridge interactions.

Main Methods:

• Ligand field molecular mechanics simulations.
• Microsecond-scale molecular dynamics simulations for free, Cu(II)-bound, and Pt(II)-bound Aβ_1-42.
• Analysis of structural parameters, secondary structure content, and salt bridge network dynamics.

Main Results:

• Both Cu(II) and Pt(II) binding significantly alter Aβ_1-42 peptide structure compared to the free monomer.
• Metals stabilize helical structures and reduce β-sheet content, consistent with experimental observations of amorphous aggregate formation.
• Distinct conformational changes were observed: free peptide adopts a globular-like structure, Pt(II) induces extended structures, and Cu(II) results in mixed conformations.
• Key salt bridges, including Asp23-Lys28 and Arg5-Asp7, show altered dynamics and distances upon metal binding, with Arg5-Asp7 eliminated in metalated systems.

Conclusions:

• Metal ions Cu(II) and Pt(II) profoundly influence Aβ_1-42 peptide conformation and dynamics.
• The observed structural changes, particularly the reduction in β-sheet content, suggest a mechanism by which metals may promote amorphous aggregation over fibril formation.
• Altered salt bridge networks indicate a disruption of interactions critical for peptide stability and potentially fibril assembly.