| Summary: | The Ab peptide is a key molecule in the development of Alzheimer’s Disease - Ab peptides form toxic aggregates in the brain. Density functional theory (DFT), Parametric Model 7 (PM7) and ligand-Field Molecular Mechanics (LFMM) methods have been used to model the interactions of a series of potential therapeutic PtII(ligand) complexes with various fragments of the Ab peptide. LFMM calculations with the AMBER forcefield were used to generate conformations of PtII-Ab6-14 via LowMode MD and results validated against BHandH. While LFMM showed insufficient agreement with DFT, the semi-empirical PM7 method displayed strong geometric and energetic agreement and was used to predict coordination preference and stable conformations of PtII(bipy) and PtII(phen) complexes. These species are shown to restrict the conformational freedom of Ab and the coordination of PtII(phen) is shown to be in agreement with experimental data. Studies of additional PtII(ligand) complexes in this manner revealed distinct preferences in metal binding mode for each of the complexes studied, with varied His Nd and His Ne coordination observed. Analysis of peptide conformations using Ramachandran plots and the STRIDE algorithm indicate that coordination of the PtII(ligand) complexes disrupts existing peptide structure in a ligand-specific fashion, interrupting or translating the turn structure, suggesting that controlling peptide structure and behaviour may be achieved via ligand design. Ligand-field molecular dynamics (LFMD) simulations of PtII(phen) -Ab16 and -Ab42 are compared to those of the metal-free peptides to investigate the influence of the PtII complex on the structure and properties of the peptide. Simulations of Ab16 and PtII(phen)-Ab16 revealed that PtII coordination does not drastically alter peptide size, but increases the occurrence of 3,10-helical conformations while disrupting hydrogen bond and salt bridge networks. Simulation data also highlights the prevalence of p-p stacking interactions between residues Phe4 and His13 with the phenanthroline ligand. Similarly, microsecond timescale simulations of PtII(phen)-Ab42 and Ab42 illustrate profound effects of PtII coordination on peptide structure; while Ab is shown to adopt collapsed conformations, PtII-Ab42 systems assume extended structures. PtII coordination also induces large changes in peptide secondary structure, particularly an increase in helical character throughout the central hydrophobic region of the peptide, considered a potential route to preventing formation of Ab fibrils. The results detailed here provide insight into the coordination of these complexes to the peptide and present a new understanding of the effects of PtII complexes on Ab.
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