Exploration of the effect of metal-ions interaction on biomolecular systems

Herein, complexes of amyloid-β (1-16) monomer with physiologically relevant metal cations such as zinc, iron, and copper, have been analysed using density functional theory DFT, semiempirical GFN2-xTB, and molecular mechanics methods. A short peptide (GHK) bound to copper was used as a model for examination of method efficacy. The semiempirical method under review was shown to reproduce the DFT energy and geometry obtained with ligand field molecular mechanics (LFMM). This made it then appropriate for further application on three different fragmentation lengths of Aβ-16 bonded to Cu(II). Accelerated molecular dynamics (aMD) simulations with the AMBER14SB force field were used to simulate the free and metal-bound Aβ-16 peptide with Zn(II), Fe(II), and Cu(II), through different binding modes. The simulation showed all metals stabilized the peptide mobility and increased the compactness in terms of RMSD, Rg, and RMSF, compared to that in the unbound monomer. The most frequent salt bridge interaction in all metal-Aβ forms, was found between Arg5 and Asp7 amino acids. The aMD simulations also showed that the number of coordinating atoms, as well as the element and/or residues, influence the overall structure, size, and stability. The observation of α-sheet secondary structure in Aβ simulations led us to extend the study to different proteins that have been reported to have this uncommon structure, also related to Aβ aggregation. DFT and semiempirical GFN2-xTB calculations were used on the modelled α�sheet residues of the peptides. The α-helix is the most stable form, compared to α-sheet and β-strand conformations, in most cases. However, in the example of peptide 1E9T, the α-sheet presents the most stable form overall, and the stability increased in the existence of cationic ions influenced mainly by the ionic charge and radius of the bound ions. Mg2+ and Ca2+ have the greatest effect on the relative stability followed by K+ , Na+ and Li+ . MD was performed on full length 1E9T peptide in a range of pH and at 310 and 498 K, in explicit solvent, with and without KCl ions. The results were consistent with literature in which α-sheet structure is a transient state between α-helix and β-sheet formation