Benchmarking of copper(II) LFMM parameters for studying amyloid-β peptides.

Area of Science:

• Computational chemistry
• Biophysics
• Metalloprotein chemistry

Background:

• Copper (II) ions are implicated in amyloid-β peptide aggregation, a hallmark of Alzheimer's disease.
• Accurate modeling of copper-peptide interactions is essential for understanding disease mechanisms and developing therapeutics.

Purpose of the Study:

• To benchmark ligand field molecular mechanics (LFMM) parameters for copper (II) interactions with the amyloid-β_1-16 peptide fragment.
• To assess the accuracy of LFMM in reproducing copper coordination geometries.

Main Methods:

• Density functional theory (DFT) optimization of small test models representing copper coordination modes.
• Ligand field molecular dynamics (LFMD) simulations of copper-bound amyloid-β_1-16.
• Geometry optimization of trajectory snapshots using DFT and the PM7 semi-empirical method.

Main Results:

• LFMM parameters show high accuracy for copper bond lengths and angles (<0.1 Å, <5° error) compared to DFT.
• LFMD simulations combined with DFT/PM7 optimization show good agreement with LFMM.
• The peptide backbone contributes most to geometric differences; the copper coordination sphere is well-reproduced by LFMM.
• PM7 method demonstrates excellent performance against LFMM (0.2 Å average RMSD).

Conclusions:

• LFMM is a reliable method for modeling copper (II) coordination in amyloid-β peptides.
• The N-terminal carbonyl moiety can act as a weakly bound fifth ligand, influencing copper coordination dynamics.
• Accurate computational modeling aids in understanding copper's role in amyloid pathology.