Spontaneous self-assembly of amyloid β (1–40) into dimers

Hashemi, Mohtadin; Zhang, Yuliang; Lv, Zhengjian; Lyubchenko, Yuri L.

doi:10.1039/c9na00380k

Cited by 13 publications

(15 citation statements)

References 85 publications

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“…Overall, we must recall that despite a constant improvement of atomistic force fields in explicit solvent, 465 there are divergences between the simulation results on kinetics and thermodynamics, 466 the impact of mutations, 467,468 the population of critical states, 469 and the shapes of oligomers. 470,471 Switching between some conformations occurs within 35 ns, as reported by FRET data. 428 The conformation of S-shape N* from the fibril structure with PDB ID 2NAO was also sampled in CG simulations 437 .…”

Section: A B D Csupporting

confidence: 60%

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

et al. 2021

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Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D) and amyotrophic lateral sclerosis (ALS) research, respectively for over many years.While SOD1 is a globular protein with a well-defined 3D structure, the Aβ, tau and α-synuclein proteins belong to the class of intrinsically disordered proteins (IDPs). IDPs are also known to play a critical role in many cellular functions such as signal transduction, cell growth, binding with DNA and RNA, and transcription, and are implicated in the development of cardiovascular problems and cancers 29 . The IDPs involved in neurodegenerative diseases have a few aggregation-prone regions and overall all IDPs have a low mean hydrophobicity and a high mean net charge 30 .IDPs are structurally flexible and lack stable secondary structures in aqueous solution. When isolated, they behave as polymers in a good solvent and their radii of gyration are well described by the Flory scaling law. 31 The insolubility and high self-assembly propensity of IDPs implicated in degenerative diseases have prevented high-resolution structural determination by solution nuclear magnetic resolution (NMR) and X-ray diffraction experiments. Local information at all aggregation steps can be, however, obtained by chemical shifts, residual coupling constants, and J-couplings from NMR, exchange hydrogen/deuterium (H/D) NMR, Raman spectroscopy; and secondary structure from fast Fourier infrared spectroscopy (FTIR) or circular dichroism (CD). Long-range tertiary contacts can be deduced from paramagnetic relaxation enhancement (PRE) NMR spectroscopy and single molecule Förster resonance energy transfer (sm-FRET), and short-range distance contacts can be extracted by cross linked residues determined by mass spectrometry (MS). Low-resolution 3D information of monomers and oligomers can be obtained by ion-mobility mass-spectrometry data (IM/MS) providing cross-collision sections, dynamic light scattering (DLS), pulse field gradient NMR spectroscopy and fluorescence correlation spectroscopy (FCS) providing hydrodynamics radius, small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS), atomic force microscopy (AFM) and transmission electron microscopy (TEM) providing height features of the aggregates, as reported by some o...

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Section: A B D Csupporting

confidence: 60%

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

et al. 2021

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“…The measurements of the stability of amyloid dimers obtained with the AFM dynamics force spectroscopy were in line with direct measurements of dimers' lifetimes performed with the use of single molecule fluorescence studies (Lv et al, 2015;Maity et al, 2017a). The structures of dimers of Aβ40 and 42 proteins and their segments were revealed with the use of all-atom Molecular Dynamics (MD) simulations (Zhang and Lyubchenko, 2014;Zhang et al, 2016;Hashemi et al, 2019).…”

Section: Introductionmentioning

confidence: 65%

AFM Probing of Amyloid-Beta 42 Dimers and Trimers

Maity

Lyubchenko

2020

Front. Mol. Biosci.

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Elucidating the molecular mechanisms in the development of such a devastating neurodegenerative disorder as Alzheimer's disease (AD) is currently one of the major challenges of molecular medicine. Evidence strongly suggests that the development of AD is due to the accumulation of amyloid β (Aβ) oligomers; therefore, understanding the molecular mechanisms defining the conversion of physiologically important monomers of Aβ proteins into neurotoxic oligomeric species is the key for the development of treatments and preventions of AD. However, these oligomers are unstable and unavailable for structural, physical, and chemical studies. We have recently developed a novel flexible nano array (FNA)-oligomer scaffold approach in which monomers tethered inside a flexible template can assemble spontaneously into oligomers with sizes defined by the number of tethered monomers. The FNA approach was tested on short decamer Aβ(14-23) peptides which were assembled into dimers and trimers. In this paper, we have extended our FNA technique for assembling full-length Aβ42 dimers. The FNA scaffold enabling the self-assembly of Aβ42 dimers from tethered monomeric species has been designed and the assembly of the dimers has been validated by AFM force spectroscopy experiments. Two major parameters of the force spectroscopy probing, the rupture forces and the rupture profiles, were obtained to prove the assembly of Aβ42 dimers. In addition, the FNA-Aβ42 dimers were used to probe Aβ42 trimers in the force spectroscopy experiments with the use of AFM tips functionalized with FNA-Aβ42 dimers and the surface with immobilized Aβ42 monomers. We found that the binding force for the Aβ42 trimer is higher than the dimer (75 ± 7 pN vs. 60 ± 3 pN) and the rupture pattern corresponds to a cooperative dissociation of the trimer. The rupture profiles for the dissociation of the Aβ42 dimers and trimers are proposed. Prospects for further extension of the FNA-based approach for probing of higher order oligomers of Aβ42 proteins are discussed.

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“…Although the oligomers of the amyloid peptide have been studied using MD simulations for more than 15 years, performing sampling for the transition from the oligomeric state to the fibrillar state and identifying the toxic oligomers is still challenging. Hashemi et al (2019) performed 3 ms aMD simulations for analyzing the dimerization of Aβ40 peptides. aMD is an enhanced-sampling method in which the potential energy terms are simplified into dispersed states and the energy barriers between adjacent energy basins are reduced (Hamelberg et al, 2004).…”

Section: Application Of Enhanced Sampling Methods On Amyloid Peptidesmentioning

confidence: 99%

On the Conformational Dynamics of β-Amyloid Forming Peptides: A Computational Perspective

Saravanan

Zhang

et al. 2020

Front. Bioeng. Biotechnol.

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Understanding the conformational dynamics of proteins and peptides involved in important functions is still a difficult task in computational structural biology. Because such conformational transitions in β-amyloid (Aβ) forming peptides play a crucial role in many neurological disorders, researchers from different scientific fields have been trying to address issues related to the folding of Aβ forming peptides together. Many theoretical models have been proposed in the recent years for studying Aβ peptides using mathematical, physicochemical, and molecular dynamics simulation, and machine learning approaches. In this article, we have comprehensively reviewed the developmental advances in the theoretical models for Aβ peptide folding and interactions, particularly in the context of neurological disorders. Furthermore, we have extensively reviewed the advances in molecular dynamics simulation as a tool used for studying the conversions between polymorphic amyloid forms and applications of using machine learning approaches in predicting Aβ peptides and aggregation-prone regions in proteins. We have also provided details on the theoretical advances in the study of Aβ peptides, which would enhance our understanding of these peptides at the molecular level and eventually lead to the development of targeted therapies for certain acute neurological disorders such as Alzheimer's disease in the future.

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Spontaneous self-assembly of amyloid β (1–40) into dimers

Abstract: Aβ40 dimer structure was identified by MD and validated using force spectroscopy data.

Cited by 13 publications

References 85 publications

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

AFM Probing of Amyloid-Beta 42 Dimers and Trimers

On the Conformational Dynamics of β-Amyloid Forming Peptides: A Computational Perspective

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