Dual effects of familial Alzheimer's disease mutations (D7H, D7N, and H6R) on amyloid β peptide: correlation dynamics and zinc binding.
Although the N-terminal region of Amyloid β (Aβ) peptides plays dual roles as metal-coordinating sites and conformational modulator, few studies have been performed to explore the effects of mutations at this region on the overall conformational ensemble of Aβ and the binding propensity of metal ions. In this work, we focus on how three familial Alzheimer's disease mutations (D7H, D7N, and H6R) alter the structural characteristics and thermodynamic stabilities of Aβ42 using molecular dynamics simulations. We observe that each mutation displays increased β-sheet structures in both N and C termini. In particular, both the N terminus and central hydrophobic region of D7H can form stable β-hairpin structures with its C terminus. The conserved turn structure at Val²⁴-Lys²⁸ in all peptides and Zn²⁺-bound Aβ42 is confirmed as the common structural motif to nucleate folding of Aβ. Each mutant can significantly increase the solvation free energy and thus enhance the aggregation of Aβ monomers. The correlation dynamics between Aβ(1-16) and Aβ(17-42) fragments are elucidated by linking the domain motions with the corresponding structured conformations. We characterize the different populations of correlated domain motions for each mutant from a more macroscopic perspective, and unexpectedly find that Zn²⁺-bound Aβ42 ensemble shares the same populations as Aβ42, indicating that the binding of Zn²⁺ to Aβ follows the conformational selection mechanism, and thus is independent of domain motions, even though the structures of Aβ have been modified at a residue level.
['Xu|Liang|L|', 'Chen|Yonggang|Y|', 'Wang|Xiaojuan|X|']
D000544:Alzheimer Disease D019943:Amino Acid Substitution D016229:Amyloid beta-Peptides D016564:Amyloid beta-Protein Precursor D001665:Binding Sites D004735:Energy Transfer D006801:Humans D057927:Hydrophobic and Hydrophilic Interactions D007700:Kinetics D008958:Models, Molecular D056004:Molecular Dynamics Simulation D009154:Mutation D010446:Peptide Fragments D066263:Protein Aggregation, Pathological D011487:Protein Conformation D017510:Protein Folding D055550:Protein Stability D012995:Solubility D013499:Surface Properties D015032:Zinc
Alzheimer's disease mutation molecular dynamics simulations free energy amyloid peptide