Conformational Distribution and α-Helix to β-Sheet Transition of Human Amylin Fragment Dimer

Qi, Ruxi; Luo, Yin; Ma, Buyong; Nussinov, Ruth; Wei, Guanghong

doi:10.1021/bm401406e

Cited by 74 publications

(107 citation statements)

References 88 publications

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“…79–81 Given these predicaments, the problem of predicting amyloid conformations using MD simulations, coarse grained, implicit, or explicit solvent description- in the solution state, without and with metal ions, on and in the membrane, in the presence and absence of AD-related mutations, and truncated fragments has drawn much attention. 82–102 Recently, a series of MD simulations provided insight into the molecular conformations of oligomeric Aβ channel structures at atomic-level resolution, 33–38,77,78,103–106 exhibiting that Aβ channels are heterogeneous, consisting of β-sheet-rich subunits with morphologies and dimensions in good agreement with the imaged AFM channels. 21,72,73 …”

Section: Introductionmentioning

confidence: 91%

Disordered amyloidogenic peptides may insert into the membrane and assemble into common cyclic structural motifs

et al. 2014

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Aggregation of disordered amyloidogenic peptides into oligomers is the causative agent of amyloid-related diseases. In solution, disordered protein states are characterized by heterogeneous ensembles. Among these, β-rich conformers self-assemble via a conformational selection mechanism to form energetically-favored cross-β structures, regardless of their precise sequences. These disordered peptides can also penetrate the membrane, and electrophysiological data indicate that they form ion-conducting channels. Based on these and additional data, including imaging and molecular dynamic simulations of a range of amyloid peptides, Alzheimer’s amyloid-β (Aβ) peptide, its disease-related variants with point mutations and N-terminal truncated species, other amyloidogenic peptides, as well as a cytolytic peptide and a synthetic gel-forming peptide, we suggest that disordered amyloidogenic peptides can also present a common motif in the membrane. The motif consists of curved, moon-like β-rich oligomers associated into annular organizations. The motif is favored in the lipid bilayer since it permits hydrophobic side chains to face and interact with the membrane and the charged/polar residues to face the solvated channel pores. Such channels are toxic since their pores allow uncontrolled leakage of ions into/out of the cell, destabilizing cellular ionic homeostasis. Here we detail Aβ, whose aggregation is associated with Alzheimer’s disease (AD) and for which there are the most abundant data. AD is a protein misfolding disease characterized by a build-up of Aβ peptide as senile plaques, neurodegeneration, and memory loss. Excessively produced Aβ peptides may directly induce cellular toxicity, even without the involvement of membrane receptors through Aβ peptide-plasma membrane interactions.

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Section: Introductionmentioning

confidence: 91%

Disordered amyloidogenic peptides may insert into the membrane and assemble into common cyclic structural motifs

et al. 2014

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“…Consequently, the helical content will transit into beta structure, consistent with our previous findings of α-helical intermediates in amyloid aggregation. 36 We also explored the conformational diversity of K18/K19 by RMSD-based cluster analysis with a cutoff equal to 0.35 nm, which produced 116 and 111 clusters for K18 and K19, respectively. Representative conformations of the top eight populated clusters are shown in Supporting Information Figure S8.…”

Section: Lettermentioning

confidence: 99%

Aβ “Stretching-and-Packing” Cross-Seeding Mechanism Can Trigger Tau Protein Aggregation

Luo

Wei

et al. 2015

J. Phys. Chem. Lett.

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There are synergistic effects of Aβ and tau protein in Alzheimer's disease. Aβ 1−42 protofibril seeds induce conversion of human tau protein into β-sheet-rich toxic tau oligomers. However, the molecular mechanisms underlying such a conformational conversion are unclear. Here, we use extensive all atom replica exchange molecular dynamics simulations to investigate the effects of preformed Aβ 1−42 protofibril on two monomeric tau constructs: K18 and K19. We found that Aβ oligomer stretches tau conformation and drastically reduces the metastable secondary structures/hydrogen bonding/salt-bridge networks in tau monomers and exposes their fibril nucleating motifs 275 VQIINK 280 and 306 VQIVYK 311 . Aβ interacting patches around Tyr10/Ile41 contribute significantly to the interactions with K18 and K19. Aβ cross-seeded tau aggregation can adopt a "stretching-and-packing" mechanism, paving the way for the next, prion-like growth step. The results provide a mechanism on the atomic level to experimental observations that tau pathogenesis is promoted by Aβ 1−42 but not by Aβ 1−40 .A myloid β (Aβ) forms extracellular senile plaques and tau protein simultaneously forms intracellular neurofibrillary tangles (NFTs) in the brain of Alzheimer's disease patients. 1,2 There is increasing evidence of independent and synergistic effects of Aβ and tau. 3−5 Classically, Aβ and tau are respectively deposited extra-and intracellularly. However, Aβ also accumulates intraneuronally 2,6 and it binds to tau to form insoluble complexes within the same neurons. 7 In the Aβ-induced tau pathology, Aβ accumulation occurs prior to tau in AD pathogenesis and triggers the conversion of tau from normal to toxic states. 3,4,6,8−15 Although mechanisms linking Aβ and tau-pathology have not been conclusively identified, several potential mechanisms have been postulated. These posit that (1) Aβ interacts directly with neuronal receptors and membranes, (2) Aβ induces inflammation via glial cells, and (3) Aβ directly seeds and propagates tau aggregation. 4 The third mechanism has recently drawn increasing attention. 4,8,16−18 Propagation of toxic, misfolded Aβ and tau bears a striking resemblance to that of the prion protein. 16,17,19 Misfolded Aβ promotes tau aggregation in vitro through direct, intermolecular interaction. 15,20,21 Intriguingly, injection of preaggregated synthetic amyloid peptides 9 or aggregated amyloid peptide enriched brain extracts 22 induced tau aggregation not only at the injection site but also in functionally connected brain regions remote from the site, which indicates that amyloid peptides can initiate and propagate tau aggregation in these regions as well. 9,22 This prion-like behavior 23,24 of Aβ and tau underscores the need for an in-depth understanding of the seeding mechanism through which Aβ induces tau pathology.It has been shown that Aβ 1−42 oligomer seeds induce the conversion of unstructured, monomeric human recombinant tau into β-sheet-rich toxic tau oligomers. 20 Previous simulations of the interactions of Aβ fibri...

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“…In this chapter, we present a brief introduction to REMD method and a practical application to study the initial dimerization step of the 11–25 fragment of human islet amyloid polypeptide (hIAPP(11–25)) aggregation [10]. We describe the detailed protocol for performing a REMD simulation and data analysis, and discuss the problems that are often encountered in REMD simulations.…”

Section: Introductionmentioning

confidence: 99%

Replica Exchange Molecular Dynamics: A Practical Application Protocol with Solutions to Common Problems and a Peptide Aggregation and Self-Assembly Example

Wei

et al. 2018

Methods in Molecular Biology

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Protein aggregation is associated with many human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and type II diabetes (T2D). Understanding the molecular mechanism of protein aggregation is essential for therapy development. Molecular dynamics (MD) simulations have been shown as powerful tools to study protein aggregation. However, conventional MD simulations can hardly sample the whole conformational space of complex protein systems within acceptable simulation time as it can be easily trapped in local minimum-energy states. Many enhanced sampling methods have been developed. Among these, the replica exchange molecular dynamics (REMD) method has gained great popularity. By combining MD simulation with the Monte Carlo algorithm, the REMD method is capable of overcoming high energy-barriers easily and of sampling sufficiently the conformational space of proteins. In this chapter, we present a brief introduction to REMD method and a practical application protocol with a case study of the dimerization of the 11-25 fragment of human islet amyloid polypeptide (hIAPP(11-25)), using the GROMACS software. We also provide solutions to problems that are often encountered in practical use, and provide some useful scripts/commands from our research that can be easily adapted to other systems.

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Conformational Distribution and α-Helix to β-Sheet Transition of Human Amylin Fragment Dimer

Cited by 74 publications

References 88 publications

Disordered amyloidogenic peptides may insert into the membrane and assemble into common cyclic structural motifs

Disordered amyloidogenic peptides may insert into the membrane and assemble into common cyclic structural motifs

Aβ “Stretching-and-Packing” Cross-Seeding Mechanism Can Trigger Tau Protein Aggregation

Replica Exchange Molecular Dynamics: A Practical Application Protocol with Solutions to Common Problems and a Peptide Aggregation and Self-Assembly Example

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