Molecular basis for chirality-regulated Aβ self-assembly and receptor recognition revealed by ion mobility-mass spectrometry

Abstract

Despite extensive efforts on probing the mechanism of Alzheimer’s disease (AD) and enormous investments into AD drug development, the lack of effective disease-modifying therapeutics and the complexity of the AD pathogenesis process suggest a great need for further insights into alternative AD drug targets. Herein, we focus on the chiral effects of truncated amyloid beta (Aβ) and offer further structural and molecular evidence for epitope region-specific, chirality-regulated Aβ fragment self-assembly and its potential impact on receptor-recognition. A multidimensional ion mobility-mass spectrometry (IM-MS) analytical platform and in-solution kinetics analysis reveal the comprehensive structural and molecular basis for differential Aβ fragment chiral chemistry, including the differential and cooperative roles of chiral Aβ N-terminal and C-terminal fragments in receptor recognition. Our method is applicable to many other systems and the results may shed light on the potential development of novel AD therapeutic strategies based on targeting the D-isomerized Aβ, rather than natural L-Aβ.

The F19W mutation reduces the binding affinity of the transmembrane Aβ11–40 trimer to the membrane bilayer

“…The collision cross section (CCS) is an important parameter for describing proteins in both experimental and computational methods. In experiments, CCS can be estimated by ion mobility mass spectrometry (IM-MS), 81,82 while computationally, it can been calculated by the IMPACT method. 67,83 CCS values of the representative structures based on IMPACT with the trajectory method are shown in Table 1.…”

Native mass spectrometry for the design and selection of protein bioreceptors for perfluorinated compounds

“…From the plots in Figure 3A and C and the corresponding feature detection in Figure S-3A and C, it is possible to observe that both proteins showed a similar TW CCSN2 (4469 ± 22 Ų and 4458 ± 22 Ų for the native untreated and delipidated hSA, respectively) until a collision energy of 825 eV, which corresponds with an applied potential difference of 55 V; afterwards a multi-step unfolding process started. 52,53 The first transition occurs between 60 and 70 V (Figure S-4) and results in a state with a TW CCSN2 of 5284 ± 22 Ų and 5262 ± 22 Ų for the untreated and 52 The second transition takes place just after 100 V and generates a state with a TW CCSN2 of 5563 ± 22 Ų and 5551 ± 22 Ų for the untreated and delipidated hSA, respectively, which corresponds to the partial unfolding of domain III. A final unfolding step occurs between 120 and 130 V, which results in a state with a TW CCSN2 of 5686 ± 22 Ų and 5641 ± 22 Ų for the untreated and delipidated hSA, respectively.…”

Fourier Transform Infrared Spectroscopy and Vibrational Circular Dichroism Assisted Elucidation of the Solution-State Supramolecular Speciation in Racemic and Enantiopure Ketoprofen

“…Indeed, the study of binding affinities for specific stereochemical configurations or conformational arrangements of drugs is a hot topic in the area of medicinal chemistry. 1,2 In addition, dimerization of a drug can also affect its diffusion parameters and certain production processes such as extraction or impregnation. 3…”