Theoretical study of copper binding to GHK peptide.

Area of Science:

• Computational chemistry
• Biophysical chemistry
• Molecular modeling

Background:

• Copper (Cu(II)) is a crucial metal ion involved in various biological processes.
• The GlyHisLys (GHK) peptide is a known copper-binding motif with potential therapeutic applications.
• Understanding the precise binding interactions between copper and GHK is essential for designing novel metallodrugs.

Purpose of the Study:

• To investigate the binding mechanism and stability of copper (Cu(II)) with the GlyHisLys (GHK) peptide.
• To evaluate the accuracy of different computational methods (ligand field molecular mechanics, DFT, semi-empirical) in predicting copper-GHK interactions.
• To assess the ability of the CREST algorithm in determining copper binding sites.

Main Methods:

• Conformational searching using molecular mechanics.
• Density Functional Theory (DFT) calculations (B3LYP-D).
• Semi-empirical calculations (GFN2-xTB).
• Conventional molecular dynamics (MD) simulations.
• Automated conformer and rotamer search using CREST.

Main Results:

• Conformational energies and geometries predicted by GFN2-xTB and B3LYP-D DFT methods showed good agreement.
• Molecular dynamics simulations confirmed the stability of copper-GHK binding over a 100 ps trajectory.
• Four equatorial copper coordination bonds were stable, while the apical bond exhibited fluxional behavior.
• The CREST algorithm successfully predicted the copper binding site from separated components.

Conclusions:

• Computational methods, including DFT and semi-empirical approaches, accurately model copper-GHK interactions.
• Copper binding to GHK is stable, with specific coordination preferences.
• The CREST algorithm is a reliable tool for predicting metal binding sites in peptides.