Abstract
The aggregation process of the Amyloidβ (Aβ) peptide is one of the central questions in Alzheimers’s research. Fluorescence-labeled single-molecule detection is a novel technique concerning the early stage investigation of Aβ aggregation, where the labeling dyes are covalently bound to the Aβ monomer. As the influence of the dye on the conformational space of the Aβ monomer can be significant, its effect on the seeding process is an open question. The applied fluorescent molecule continuously switches between an active (ON) and an inactive (OFF) state, where the latter supports an extra rotational restriction at many commercially available dyes. However, only a few theoretical studies simulated the Aβ monomer in the presence of a dye and none of them considered the difference between the ON and the OFF states. Therefore, we examined the impact of a selected fluorescence dye (Alexa 568) on the conformational space of the monomeric Aβ(1–42) peptide in its ON and OFF state by replica exchange molecular dynamic simulations. Investigations on secondary structure elements as well as dye-peptide contact analysis for the monomers are presented. Experimental and theoretical NMR shifts were contrasted to qualify the calculation protocol and theoretical values of the labeled and the non-labeled peptide were also compared. We found that the first five residues have higher helical propensity in the presence of the dye, and electrostatic properties could strongly affect the connection between the dye and the peptide parts.
Highlights
Alzheimer’s disease (AD) is one of the most common types of neurodegenerative disorder in the elderly population [1,2]
We found a strong interaction between the SO3(−) group at the dye and the this proximity, we found a strong interaction between the SO3 (−) group at the dye and the positively positively charged guanidino group from the arginine. This connection is a good example of why we charged guanidino group from the arginine. This connection is a good example of why we focused focused on the geometrical contacts: it is hard to distinguish in this case, whether it is a on the geometrical contacts: it is hard to distinguish in this case, whether it is a hydrogen bond hydrogen bond connection, or whether we should handle it as an electrostatic zwitterionic connection, or whether we should handle it as an electrostatic zwitterionic interaction
In the present study we investigated the effect of covalently bounded fluorescence dye molecules on the conformal space of the 42 units long monomeric amyloid β (Aβ) peptide
Summary
Alzheimer’s disease (AD) is one of the most common types of neurodegenerative disorder in the elderly population [1,2]. AD can be characterized by the accumulation and aggregation of amyloid β (Aβ) peptides in the central nervous system. Aβ peptide is cut out from the Amyloid. Recent studies have shown that there is a structural difference between fibrils seeded in vitro from. The mechanism of fibril formation is not trivial and extremely difficult to characterize experimentally due to the heterogeneity and transient nature of the initial oligomers [5,6]. It is widely accepted that early stage oligomerization could be more toxic than mature fibrils due to the interaction with different synaptic receptors [7,8]
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