We describe solid-state nuclear magnetic resonance (NMR) measurements on fibrils formed by the 40-residue β-amyloid peptide associated with Alzheimer's disease (Aβ1-40) that place constraints on the identity and symmetry of contacts between in-register, parallel β-sheets in the fibrils. We refer to these contacts as internal and external quaternary contacts, depending on whether they are within a single molecular layer or between molecular layers. The data include (1) two-dimensional 13C-13C NMR spectra that indicate internal quaternary contacts between side chains of L17 and F19 and side chains of I32, L34, and V36, as well as external quaternary contacts between side chains of I31 and G37; (2) two-dimensional 15N-13C NMR spectra that indicate external quaternary contacts between the side chain of M35 and the peptide backbone at G33; (3) measurements of magnetic dipole−dipole couplings between the side chain carboxylate group of D23 and the side chain amine group of K28 that indicate salt bridge interact...

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Experimental Constraints on Quaternary Structure in Alzheimer's β-Amyloid Fibrils†

The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis

The amyloid-beta(1-42) (Abeta42) peptide rapidly aggregates to form oligomers, protofibils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. We show that low-temperature and low-salt conditions can stabilize disc-shaped oligomers (pentamers) that are substantially more toxic to mouse cortical neurons than protofibrils and fibrils. We find that these neurotoxic oligomers do not have the beta-sheet structure characteristic of fibrils. Rather, the oligomers are composed of loosely aggregated strands whose C termini are protected from solvent exchange and which have a turn conformation, placing Phe19 in contact with Leu34. On the basis of NMR spectroscopy, we show that the structural conversion of Abeta42 oligomers to fibrils involves the association of these loosely aggregated strands into beta-sheets whose individual beta-strands polymerize in a parallel, in-register orientation and are staggered at an intermonomer contact between Gln15 and Gly37.

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Structural conversion of neurotoxic amyloid-[beta]1-42 oligomers to fibrils

Molecular Structure of β-Amyloid Fibrils in Alzheimer’s Disease Brain Tissue

dipolar-assisted rotational resonance in magic-angle spinning NMR

Two recently proposed 13C–13C recoupling methods under magic angle spinning (MAS), resonant interference recoupling (RIR), and 13C–1H dipolar-assisted rotational resonance (DARR), are examined on a common theoretical foundation using the average Hamiltonian theory. In both methods, a rf field is applied on not 13C but 1H to recouple the 13C–1H dipolar interactions, and spectral overlap necessary to conserve energy for 13C–13C polarization transfer is achieved by the 13C–1H dipolar line broadening. While DARR employs time-independent 13C–1H interactions recoupled by suitable rf irradiation to 1H spins, RIR uses time-dependent 13C–1H interactions modulated appropriately by 1H rf irradiation. There are two distinct cases where 13C–1H line broadening realizes 13C–13C spectral overlap. For a pair of a carbonyl or aromatic carbon and an aliphatic carbon, spectral overlap can be achieved between one of the spinning sidebands of the former 13C resonance and the 13C–1H dipolar powder pattern of the latter. On the ...

/pdf/13c-1h-dipolar-driven-13c-13c-recoupling-without-13c-rf-54m3w2swzo.pdf

13C–1H dipolar-driven 13C–13C recoupling without 13C rf irradiation in nuclear magnetic resonance of rotating solids

13C–13C polarization transfer by resonant interference recoupling under magic-angle spinning in solid-state NMR

Solid-state photodimerization of 9-methylanthracene as studied by solid-state 13C NMR.

The mechanism of the optical resolution of gamma-valerolactone (VAL) enantiomers by enclathration in cholic acid (CA) channels was investigated. 13C cross-polarization magic-angle spinning spectra of CA/VAL inclusion compounds show four methyl 13C peaks of VAL with different intensities depending on the enantiomeric ratios. The four peaks were assigned to the inner and end (S)-(-)-enantiomers (S) in the S domain and the inner and end (R)-(+)-enantiomers (R). The relative intensities of the four methyl 13C peaks cannot be explained by the random process model for inclusion but are successfully reproduced by assuming the first-order Markov process, in which the inclusion probabilities of S and R depend on which enantiomer has precedingly entered the CA channel. The probability p(S/S) that two S enantiomers successively enter a channel is thus found to be 83%, and p(R/R) is 50%. The large probability of p(S/S) indicates that once an S enantiomer enters a channel, it become easy for other S enantiomers to successively enter the channel, and thus the large enantiomeric excess of S is obtained. The inclusion probabilities of S and R were confirmed by 1D 13C-13C polarization-transfer experiments among the four methyl carbons of VAL in the CA channel. Further, we found that the 13C line widths and peak positions of the CA tail group change depending on the enantiomeric ratio. We concluded that once S is included, it changes the conformation of the CA tail group so that other S enantiomers become easy to successively enter the channel.

Sequential Arrangement of γ-Valerolactone Enantiomers Enclathrated in Cholic Acid Channels as Studied by 13C Solid-State NMR: Elucidation of the Optical Resolution Mechanism

Shinji Nakamura

Papers

dipolar-assisted rotational resonance in magic-angle spinning NMR

13C–1H dipolar-driven 13C–13C recoupling without 13C rf irradiation in nuclear magnetic resonance of rotating solids

13C–13C polarization transfer by resonant interference recoupling under magic-angle spinning in solid-state NMR

Solid-state photodimerization of 9-methylanthracene as studied by solid-state 13C NMR.

Sequential Arrangement of γ-Valerolactone Enantiomers Enclathrated in Cholic Acid Channels as Studied by 13C Solid-State NMR: Elucidation of the Optical Resolution Mechanism