Nanomechanics of individual amyloid fibrils using atomic force microscopy

Zhou, Xingfei; Cui, ChengYi; Zhang, JinHai; Liu, Jianhua; Liu, Jingsong

doi:10.1007/s11434-010-3201-9

Cited by 10 publications

(11 citation statements)

References 25 publications

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“…Similar findings were observed for Aβ oligomers using all atom MD simulations, namely, extending the Aβ (9-42) protofilament length was found to introduce an overtwist in the protofibril structure which in turn resulted in a high deviation from the starting conformation and eventually a breakage of the β-sheets. − Prior MD analyses on the deformation of Aβ (1-40) amyloid fibrils have also revealed that fibril breakage under mechanical loading ( i.e. , compressive and tensile strain) was preceded by torsional twisting deformation. ,, Besides, results from AFM and nanoindentation analysis have indicated that twisted β-sheets of hαS and glucagon are weaker or have lower elasticity modulus at the twist sections. Based on the simulation findings, any vulnerable point within the cross-β structure consistently reduces the ability of fibrils to withstand physical stress. , …”

Section: Results and Discussionsupporting

confidence: 58%

Crocin Inhibits the Fibrillation of Human α-synuclein and Disassembles Mature Fibrils: Experimental Findings and Mechanistic Insights from Molecular Dynamics Simulation

Saffari

Amininasab

2021

ACS Chem. Neurosci.

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The aggregation of human alpha-synuclein (hαS) is pivotally implicated in the development of most types of synucleinopathies. Molecules that can inhibit or reverse the aggregation process of amyloidogenic proteins have potential therapeutic value. The anti-aggregating activity of multiple carotenoid compounds has been reported over the past decades against a growing list of amyloidogenic polypeptides. Here, we aimed to determine whether crocin, the main carotenoid glycoside component of saffron, would inhibit hαS aggregation or could disassemble its preformed fibrils. By employing a series of biochemical and biophysical techniques, crocin was exhibited to inhibit hαS fibrillation in a dose-dependent fashion by stabilizing very early aggregation intermediates in off-pathway non-toxic conformations with little β-sheet content. We also observed that crocin at high concentrations could efficiently destabilize mature fibrils and disassemble them into seeding-incompetent intermediates by altering their β-sheet conformation and reshaping their structure. Our atomistic molecular dynamics (MD) simulations demonstrated that crocin molecules bind to both the non amyloid-β component (NAC) region and C-terminal domain of hαS. These interactions could thereby stabilize the autoinhibitory conformation of the protein and prevent it from adopting aggregation-prone structures. MD simulations further suggested that ligand molecules prefer to reside longitudinally along the fibril axis onto the edges of the inter-protofilament interface where they establish hydrogen and hydrophobic bonds with steric zipper stabilizing residues. These interactions turned out to destabilize hαS fibrils by altering the interstrand twist angles, increasing the rigidity of the fibril core, and elevating its radius of gyration. Our findings suggest the potential pharmaceutical implication of crocin in synucleinopathies.

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Section: Results and Discussionsupporting

confidence: 58%

Crocin Inhibits the Fibrillation of Human α-synuclein and Disassembles Mature Fibrils: Experimental Findings and Mechanistic Insights from Molecular Dynamics Simulation

Saffari

Amininasab

2021

ACS Chem. Neurosci.

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“…This large range in moduli is common for amyloid fibrils and indicative of their structural heterogeneity. For example, AFM‐based nanoindentation studies estimated that the elastic moduli of glucagon amyloid fibrils range from 0.72 ± 0.80 GPa to 1.26 ± 0.62 GPa under small compressive forces while the moduli of insulin amyloid fibrils ranged from 5 to 50 MPa …”

Section: Measuring Mechanical Properties Of Single Molecules and Filamentioning

confidence: 99%

Polymer physics inspired approaches for the study of the mechanical properties of amyloid fibrils

Volpatti

Knowles

2013

J Polym Sci B Polym Phys

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Amyloid structures constitute a class of highly ordered nanomaterials formed by insoluble protein aggregates. These aggregates are characterized by a cross-b structural motif in which b-sheets are oriented perpendicular to the fibril axis and bound together by a dense hydrogen bonding network. Although they have been associated with several neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, amyloid fibrils have also been found in many physiologically beneficial roles, for instance in adhesives and hormone storage. Inspired by this natural occurrence of functional amyloid, the hierarchal self-assembly of these structures has recently been used to develop artificial biomaterials for applications in medicine and nanotechnology. In order to realize the full potential of amyloids as functional materials, it is important to understand their fundamental mechanical properties. This review explores a range of experimental strategies to determine the mechanical properties of amyloid fibrils and discusses the results in the context of polymer physics concepts.

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“…Therefore, studying their shell mechanical properties, especially the mechanical property of single NP-P- 17 and force−volume mapping can be used to measure the elastic modulus of protein molecules and fibers. 18,19 By combining AFM with reflection interference contrast microscopy, the elastic modulus of polymer capsules can be measured. 20 We measured the mechanical properties of hollow silica spheres by combining AFM and reflection interference contrast microscopy.…”

Section: Introductionmentioning

confidence: 99%

Mechanical Properties of Sub-Microbubbles with a Nanoparticle-Decorated Polymer Shell

et al. 2019

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Nanoparticle-decorated polymer-coated sub-microbubbles (NP-P-coated SMBs), as proved, have shown promising application prospects in ultrasound imaging, magnetic resonance imaging, drug delivery, and so forth. However, the quantitative evaluation of the stability and mechanical properties of single NP-P-coated SMB is absent. Here, we first reported the stiffness and Young’s modulus of single NP-P-coated SMB obtained by the PeakForce mode of atomic force microscopy. Such NP-P-coated SMBs could maintain perfect spherical shapes and have a thinner shell thickness (about 10 nm), as determined by characterization using a transmission electron microscope. Young’s modulus of NP-P-coated SMBs is about 4.6 ± 1.2 GPa, and their stiffness is about 15.0 ± 3.1 N/m. Both modulus and stiffness are obtained from the linear region in the force–deformation curve and are nearly independent of their sizes. These results should be very useful to evaluate their stability, which plays a key role in maintaining the shell drug loading and acoustic capabilities.

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Nanomechanics of individual amyloid fibrils using atomic force microscopy

Cited by 10 publications

References 25 publications

Crocin Inhibits the Fibrillation of Human α-synuclein and Disassembles Mature Fibrils: Experimental Findings and Mechanistic Insights from Molecular Dynamics Simulation

Crocin Inhibits the Fibrillation of Human α-synuclein and Disassembles Mature Fibrils: Experimental Findings and Mechanistic Insights from Molecular Dynamics Simulation

Polymer physics inspired approaches for the study of the mechanical properties of amyloid fibrils

Mechanical Properties of Sub-Microbubbles with a Nanoparticle-Decorated Polymer Shell

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