Length‐Dependent Manifestation of Vibration Modes Regulates a Specific Intermediate Morphology of Aβ17‐42 in Different Environments

Abstract

Various cytotoxic mechanisms for neurodegenerative disease are induced by specific conformations of Aβ intermediates. The efforts to understand the diverse intermediate forms of amyloid oligomers have been focused on understanding the aggregation mechanism of specific morphologies for Aβ intermediates. However, these are still not easy tasks to be accomplished because the diverse conformations of Aβ intermediates can be altered during the aggregation process, even though the same Aβ monomers are present. Thus, efforts to reveal the conformational change mechanism could be a fundamental process to understand the formation of diverse Aβ intermediate conformations. Here, we evaluate the conformational characteristics of Aβ fibrillar oligomers in different environments according to the length. We observed that Aβ fibrillar oligomers optimize their inherent hydrogen bonds and configurational entropy to stabilize their structure according to the simulation time and their length increase. In addition, we revealed the role of the expressed vibration mode shape in the fibrillar oligomers' elongation and deformation processes. Our results suggest that limitations in amyloid oligomer growth and transformations of their morphologies can be regulated and controlled by modifying the vibration features.

The Formation Mechanism of Segmented Ring-Shaped Aβ Oligomers and Protofibrils

“…could affect the stability of Aβ oligomers in the fibrillization process. − Most of the structural characteristics of Aβ showed a relation with fibrillization. However, irregular conformations, that do not seem to be associated with fibrillization, were often observed in the case of long Aβ oligomers. ,, Especially, as we have revealed in our previous studies, the over 20-mer Aβ oligomer exhibited an excessively bent conformation that could be clearly distinguished from Aβ proto-fibrils. − Single oligomer MD simulations may be regarded as a low oligomer concentration environment, because the single oligomer cannot aggregate with other oligomers. Therefore, we conjecture that this bent oligomer might be associated with the manifestation of different morphologies (i.e., annular or spherical oligomers) at low Aβ concentration.…”

“…However, irregular conformations, that do not seem to be associated with fibrillization, were often observed in the case of long Aβ oligomers. 35,50,51 Especially, as we have revealed in our previous studies, the over 20-mer Aβ oligomer exhibited an excessively bent conformation that could be clearly distinguished from Aβ proto-fibrils. 34−36 Single oligomer MD simulations may be regarded as a low oligomer concentration environment, because the single oligomer cannot aggregate with other oligomers.…”

“…It was our conjecture that the observed bent p3 oligomer might be an intermediate state during the formation of segmented-ring-shaped oligomers. Previously, it was observed that stable amyloid structures from MD simulations often presented such bent morphologies. − In this regard, we assumed that these bent amyloid oligomers might be related to the deformation of p3 oligomers depicted in Figure . To characterize the structure of these bent p3 oligomers, we carried out the MD simulations and computational analyses.…”

“…The deformation of proteins is associated with local motion of the backbone structure. Previously, it was suggested that deformation of the amyloid oligomer could be induced by the vibration characteristics of the amyloid’s backbone structure. , The torsional and bending vibration mode in the low frequency region, except for translational and rotational motion, could affect the deformation of the amyloid backbone structure. ,, To evaluate how these local motions could affect the manifestation of the deformed p3 oligomeric structure, we calculated the interlayer twisted angle (related to torsional motion) and the p3 oligomer’s curvature (related to bending motion). The interlayer angle and the curvature of a p3 oligomer are depicted in Figure S2.…”

“…As shown in previous studies, deformation of Aβ oligomers occurs when the existing partial hydrogen bonds are broken, or new hydrogen bonds are formed, inducing local motion of the partial regions. 35,49,51,52 Such deformation has been related to the vibration mode shape of the protein structure. 35,52 The proto-fibrillar morphology was observed in case I; the bent morphology was observed in cases II, III, and IV; and the overtwisted morphology was observed in case V (Figure 4A).…”