1. Amyloid fibril formation by A beta 16-22, a seven-residue fragment of the Alzheimer's beta-amyloid peptide, and structural characterization by solid state NMR
J J Balbach, Y Ishii, O N Antzutkin, R D Leapman, N W Rizzo, F Dyda, J Reed, R Tycko Biochemistry. 2000 Nov 14;39(45):13748-59. doi: 10.1021/bi0011330.
The seven-residue peptide N-acetyl-Lys-Leu-Val-Phe-Phe-Ala-Glu-NH(2), called A beta(16-22) and representing residues 16-22 of the full-length beta-amyloid peptide associated with Alzheimer's disease, is shown by electron microscopy to form highly ordered fibrils upon incubation of aqueous solutions. X-ray powder diffraction and optical birefringence measurements confirm that these are amyloid fibrils. The peptide conformation and supramolecular organization in A beta(16-22) fibrils are investigated by solid state (13)C NMR measurements. Two-dimensional magic-angle spinning (2D MAS) exchange and constant-time double-quantum-filtered dipolar recoupling (CTDQFD) measurements indicate a beta-strand conformation of the peptide backbone at the central phenylalanine. One-dimensional and two-dimensional spectra of selectively and uniformly labeled samples exhibit (13)C NMR line widths of <2 ppm, demonstrating that the peptide, including amino acid side chains, has a well-ordered conformation in the fibrils. Two-dimensional (13)C-(13)C chemical shift correlation spectroscopy permits a nearly complete assignment of backbone and side chain (13)C NMR signals and indicates that the beta-strand conformation extends across the entire hydrophobic segment from Leu17 through Ala21. (13)C multiple-quantum (MQ) NMR and (13)C/(15)N rotational echo double-resonance (REDOR) measurements indicate an antiparallel organization of beta-sheets in the A beta(16-22) fibrils. These results suggest that the degree of structural order at the molecular level in amyloid fibrils can approach that in peptide or protein crystals, suggest how the supramolecular organization of beta-sheets in amyloid fibrils can be dependent on the peptide sequence, and illustrate the utility of solid state NMR measurements as probes of the molecular structure of amyloid fibrils. A beta(16-22) is among the shortest fibril-forming fragments of full-length beta-amyloid reported to date, and hence serves as a useful model system for physical studies of amyloid fibril formation.
2. Molecular dynamics simulations of amyloid-β(16-22) peptide aggregation at air-water interfaces
Hisashi Okumura, Satoru G Itoh J Chem Phys. 2020 Mar 7;152(9):095101. doi: 10.1063/1.5131848.
Oligomers of amyloid-β (Aβ) peptides are known to be related to Alzheimer's disease, and their formation is accelerated at hydrophilic-hydrophobic interfaces, such as the cell membrane surface and air-water interface. Here, we report molecular dynamics simulations of aggregation of Aβ(16-22) peptides at air-water interfaces. First, 100 randomly distributed Aβ(16-22) peptides moved to the interface. The high concentration of peptides then accelerated their aggregation and formation of antiparallel β-sheets. Two layers of oligomers were observed near the interface. In the first layer from the interface, the oligomer with less β-bridges exposed the hydrophobic residues to the air. The second layer consisted of oligomers with more β-bridges that protruded into water. They are more soluble in water because the hydrophobic residues are covered by N- and C-terminal hydrophilic residues that are aligned well along the oligomer edge. These results indicate that amyloid protofibril formation mainly occurs in the second layer.
3. Hydrodynamic effects on β-amyloid (16-22) peptide aggregation
Mara Chiricotto, Simone Melchionna, Philippe Derreumaux, Fabio Sterpone J Chem Phys. 2016 Jul 21;145(3):035102. doi: 10.1063/1.4958323.
Computer simulations based on simplified representations are routinely used to explore the early steps of amyloid aggregation. However, when protein models with implicit solvent are employed, these simulations miss the effect of solvent induced correlations on the aggregation kinetics and lifetimes of metastable states. In this work, we apply the multi-scale Lattice Boltzmann Molecular Dynamics technique (LBMD) to investigate the initial aggregation phases of the amyloid Aβ16-22 peptide. LBMD includes naturally hydrodynamic interactions (HIs) via a kinetic on-lattice representation of the fluid kinetics. The peptides are represented by the flexible OPEP coarse-grained force field. First, we have tuned the essential parameters that control the coupling between the molecular and fluid evolutions in order to reproduce the experimental diffusivity of elementary species. The method is then deployed to investigate the effect of HIs on the aggregation of 100 and 1000 Aβ16-22 peptides. We show that HIs clearly impact the aggregation process and the fluctuations of the oligomer sizes by favouring the fusion and exchange dynamics of oligomers between aggregates. HIs also guide the growth of the leading largest cluster. For the 100 Aβ16-22 peptide system, the simulation of ~300 ns allowed us to observe the transition from ellipsoidal assemblies to an elongated and slightly twisted aggregate involving almost the totality of the peptides. For the 1000 Aβ16-22 peptides, a system of unprecedented size at quasi-atomistic resolution, we were able to explore a branched disordered fibril-like structure that has never been described by other computer simulations, but has been observed experimentally.
