Direct Dynamics Simulations of Fragmentation of a Zn(II)-2Cys-2His Oligopeptide. Comparison with Mass Spectrometry Collision-Induced Dissociation

Abnormalities in zinc metabolism have been linked to many diseases, including different kinds of cancers and neurological diseases. The present study investigates the fragmentation pathways of a zinc chaperon using a model peptide with the sequence acetyl-His1-Cys2-Gly3-Pro4-Tyr5-His6-Cys7 (analog methanobactin peptide-5, amb5). DFT/M05-2X and B3LYP geometry optimizations of [amb5–3H+Zn­(II)] predicted three lowest energy conformers with different chelating motifs. Direct dynamics simulations, using the PM7 semiempirical electronic structure method, were performed for these conformers, labeled a, b, and c, to obtain their fragmentation pathways at different temperatures in the range 1600–2250 K. The simulation results were compared with negative ion mode mass spectrometry experiments. For conformer a, the number of primary dissociation pathways are 11, 14, 24, 70, and 71 at 1600, 1750, 1875, 2000, and 2250 K, respectively. However, there are only 6, 10, 13, 14, and 19 pathways corresponding to these temperatures that have a probability of 2% or more. For conformer b, there are 67 pathways at 2000 K and 71 pathways at 2250 K. For conformer c, 17 pathways were observed at 2000 K. For conformer a, for two of the most common pathways involving C–C bond dissociation, Arrhenius parameters were calculated. The frequency factors and activation energies are smaller than those for C–C homolytic dissociation in alkanes due to increased stability of the product ions as a result of hydrogen bonding. The activation energies agree with the PM7 barriers for the C–C dissociations. Comparison of the simulation and experimental fragmentation ion yields shows the simulations predict double or triple cleavages of the backbone with Zn­(II) retaining its binding sites, whereas the experiment exhibits single cleavages of the backbone accompanied by cleavage of two of the Zn­(II) binding sites, resulting in b- and y-type ions.