Structure Properties Of Aβ_1-42 Monoer And Oligomer At Different P H Values

Alzheimer disease is a common neurological degeneration disease. As reported, Aβ1-42 is the main component of amyloid protein oligomer, and it’s ratio in amyloid protein reaching up to 90 percentage. As the main domain of metal combination, Aβ1-16 plays a key role in the understanding of the Aβ aggregation induced by metal ions and draws considerable attention. There are many controversies in the model of metal ion bound Aβ, especially in the involved number and sites of His residues in Cu2+ coordination models. Disproving these arguments is hard so far due to amorphous structure of the Aβ1-16 segment. Herein, we employ a center-distance statistical method(CDSM) to analyze the available coordination sites and their order of priority upon the case of Cu2+ bound a mice(m) and human(h) Aβ1-16(m/hAβ1-16) monomer as well as their dimers under different acidity by employing both annealing simulation and the classic dynamics simulation. In the CDSM, N atom in the N-terminal is taken as the center, and active sites in the range of 6? around the center are counted. Based on the CDSM, His6 in mAβ1-16 is predicted priority site to combine with Cu2+ when pH<6.7, while His6 and His14 almost share the equal probability to combine Cu2+ when pH> 6.7. In hAβ1-16, both His6 and His13 will combine with Cu2+ in the range of pH = 6.0~7.4. His13 becomes the main site to combine with Cu2+ when pH>7.5 however. The present predictions provide a better answer for those disputed observations in experiments, indicating the CDSM can be also used to predict other disordered peptide segment when a Cu2+ is involved. Meanwhile, the comparison of mAβ1-16 with hAβ1-16 reveals that the mutation of three residues in mAβ plays key roles for mice to develop less Alzheimer’s disease:(1) a bend configuration reinforced by the salt bridge between Arg5 and Asp7/Glu11(sometimes Asp1) in hAβ disappears in mAβ because Arg5 in hAβ is replaced by Gly5, whereas the bend configuration is the key to shorten the distances among active sites for Cu2+ to bind.(2) The thirteenth residue in mAβ1-16 is Arg13 instead of His13 in hAβ1-16, which may form a salt bridge with Glu11/Asp7 in mAβ1-16 at pH = 6.0~6.6. The replacement of His13 by Arg13 in mAβ1-16 not only can reduce the number of potential sites for the metal ion to coordinate, but also hinder His14 to involve in the combination of metal ion spatially if the salt bridge is generated.(3) It is harder for His from another chain to combine with Cu2+ in mAβ1-16 dimer, it is toilless in hAβ1-16 dimer to form such kind of coordination sphere however.After discussion for the hydrophilic Aβ1-16 region, we employ full-length Aβ1-42 with two hydrophobic regions in order to further probe acidity effect on the aggregation of real amyloid protein and find out how the hydrophobic regions self-aggregate under such an acidity. Because both experiment and simulation have proved that weak acid is helpful for aggregation of Aβ protein, a model composed of full-length Aβ1-42 instead of Aβ1-16 is a more suitable to explain the AD. Herein following simulation models include monomer, trimer, pentamer Aβ1-42 conformers and their acidic derivatives at pH=4.0, 5.0, 6.0, 6.5 and 7.0. Comparisons with β-sheet ratio of monomr and trimer at above different pH values reveal that Aβ1-42 is more easier to aggregate at pH=5.0~6.0, indicating that neutral Aβ(net charge is about zero) do be apt to aggregrate. The aggregration of pentamer is less influenced by differernt acidic conditions because the β-sheet ratios keep nearly constant at different pH values. The more chains gather, the less the structure would be affected by pH value changes, and thus the more stable the structure would be. We also find that the number of hydrogen bond between intermolecular beta-strand is correlated positively with the ratio of beta-sheet. Higher ratio of beta-sheet implies more hydrogen bonds between intermolecular beta-sheet strands. Analyses reveal that salt bridge D23-K28 plays an important role in stability of hairpin structure and that distance between Cγ of D23 and Nζ of K23 is associated with the fold structure of hydrophobic region. The closer the distance between the salt bridge is, the higher ratio of beta-sheet will be, and the better fold structure of hairpin remains. Our results for salt bridges further confirm that Aβ1-42 is easier to gather at weak acid condition. Twist angle calculations show that pentamer at pH=4.0 shows a better fiber strength and stability. The ratio of β-sheet is higher in this condition.