The molecular mechanism of conformational changes of the triplet prion fibrils for pH

Choi, Hyunsung; Chang, Hyun Joon; Shin, Yongwoo; Kim, Jae In; Park, Harold S.; Yoon, Giwan; Na, Sungsoo

doi:10.1039/c5ra08015k

Cited by 14 publications

(13 citation statements)

References 25 publications

(81 reference statements)

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“…Our recent study [19] reports that the size-dependent elastic properties of prion fibrils provide an insight into their critical size of infectious prion fibrils. In addition, a recent study by Choi et al [28] reports the mechanical and structural characteristics of prion fibrils under different pH conditions with using elastic network model (ENM)-based normal mode analysis.…”

Section: Introductionmentioning

confidence: 99%

Mechanical Deformation Mechanisms and Properties of Prion Fibrils Probed by Atomistic Simulations

et al. 2017

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Prion fibrils, which are a hallmark for neurodegenerative diseases, have recently been found to exhibit the structural diversity that governs disease pathology. Despite our recent finding concerning the role of the disease-specific structure of prion fibrils in determining their elastic properties, the mechanical deformation mechanisms and fracture properties of prion fibrils depending on their structures have not been fully characterized. In this work, we have studied the tensile deformation mechanisms of prion and non-prion amyloid fibrils by using steered molecular dynamics simulations. Our simulation results show that the elastic modulus of prion fibril, which is formed based on left-handed β-helical structure, is larger than that of non-prion fibril constructed based on right-handed β-helix. However, the mechanical toughness of prion fibril is found to be less than that of non-prion fibril, which indicates that infectious prion fibril is more fragile than non-infectious (non-prion) fibril. Our study sheds light on the role of the helical structure of amyloid fibrils, which is related to prion infectivity, in determining their mechanical deformation mechanisms and properties.

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Section: Introductionmentioning

confidence: 99%

Mechanical Deformation Mechanisms and Properties of Prion Fibrils Probed by Atomistic Simulations

et al. 2017

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“…In addition, the β‐amyloid fibrillar structure could be regarded as a continuous beam at a certain amount of length, which enabled us to gain further insight on the structural properties e. g. elastic modulus, bending rigidity, persistence length etc. Furthermore, we discovered in our previous works that these properties of amyloids are related to the dynamics of amyloid backbone structures, and these motions of amyloid backbone structure could be presented with their fundamental vibrational mode shapes ,…”

Section: Resultsmentioning

confidence: 96%

“…The simplest analysis techniques, principle component analysis (PCA) and elastic network model (ENM), are usually utilized for the analysis of essential motion and mechanical features of protein structures. These analysis techniques revealed that amyloid fibril morphology changes and mechanical properties can be analyzed by mechanically induced vibrational characteristics ,. In the basic theory of mechanical vibration, bending, torsional, and axial mode shapes are considered, as they are the fundamental mode shapes that are expressed in a low vibration region.…”

Section: Resultsmentioning

confidence: 99%

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

Choi

Yoon

2018

ChemPhysChem

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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.

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“…In the first section, the seeding mechanisms of prions for the homogenous and heterogeneous fibrils are introduced, and the Figure 18. Cumulative overlap between normal modes calculated from pH 2 model and direction vector between pH 2 and pH 3 model [64]. molecular structure differences in the assembly process of amyloid fibrils under environmental conditions are described in the second section.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, left-handed prion fibrils had more local contacts than nonprion fibrils, which are consistent with the results of a previous study analyzing hydrogen bonds. Triplet fibrils were also examined by ENM and NMA [64]. In this study, prion triplet fibrils were compared at pH 2 and 3.…”

Section: Simulation Methodsmentioning

confidence: 99%

Structure-Property Relationship of Amyloidogenic Prion Nanofibrils

Lee¹,

Choi²,

Kim³

et al. 2017

Prion - An Overview

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The structure and its property for the prion nanofibrils, which exhibit self-assembled steric zipper, amyloid fibrils, are described in this chapter. There is the belief of origin for the infectiousness of the prion can be its molecular structure. It is due to the amyloid toxicity, which is related to its beta sheet rich molecular structure and self-aggregated long fibrils. There is evidence that the difference between PrP c and PrP sc is transitioned beta sheet from alpha helix to self-assemble and then to the amyloidogenic fibrils. Therefore, the scope of this chapter is the amyloidogenic structural characteristics of prion fibrils and its relationship to the property. The molecular structural characteristics can be changed by properties such as affinity, toxicity, infectivity, and so on, so this is a key factor to understand the origin of prion disease and develop the therapeutic strategy. One of the main properties of amyloid fibrils that we want to describe here is mechanical property such as dynamic property and material property for prion nanofibrils. This chapter can shed light on understanding the infectious characteristics of prion and the relationship of its molecular structures.

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The molecular mechanism of conformational changes of the triplet prion fibrils for pH

Cited by 14 publications

References 25 publications

Mechanical Deformation Mechanisms and Properties of Prion Fibrils Probed by Atomistic Simulations

Mechanical Deformation Mechanisms and Properties of Prion Fibrils Probed by Atomistic Simulations

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

Structure-Property Relationship of Amyloidogenic Prion Nanofibrils

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