Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide

Xing, Yanting; Pilkington, Emily H.; Wang, Miaoyi; Nowell, Cameron J.; Käkinen, Aleksandr; Sun, Yunxiang; Wang, Bo; Davis, Thomas P.; Ding, Feng; Ke, Pu Chun

doi:10.1039/c7cp06670h

Cited by 15 publications

(9 citation statements)

References 42 publications

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“…Similar behavior is observed in a host of amyloid‐prone peptides in vitro , including uperin 3.5, which adopts an α‐helical structure in membrane‐like environments . Although, as observed for hIAPP, the surrounding lipid environment might also disrupt peptide aggregation . Electrolytes can play a crucial role in the stabilization of peptide secondary structure and fibril formation by screening the charges on the residues and thus reducing the surface tension .…”

Section: Introductionsupporting

confidence: 55%

Mechanistic insight into the early stages of amyloid formation using an anuran peptide

et al. 2019

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Uperin 3.5 is a short antimicrobial peptide consisting of 17 Amino acids (GVGDL5IRKAV10SVIKN15IV‐NH2) and is naturally obtained from the skin secretion of Uperoleia mjobergii. It is unusual, as it does not aggregate in pure water, but self‐aggregates to form amyloid fibrils in saline buffer. Hence, it can be used as a model peptide to understand the role of salt in the early stages of amyloid fibril formation. We use molecular dynamics simulations and direct experimental evidence from circular dichroism measurements to investigate the effect of NaCl concentration on interpeptide interactions during the early stages of uperin 3.5 aggregation in water. Our simulations show that addition of salt leads to screening of the positive charges on the R7, K8, and K14 residues by chloride counter‐ions, which in turn results in an increase in the net attraction between the predominantly hydrophobic AVSVI segments of the polypeptide. With addition of salt, changes in interpeptide interactions are accompanied by significant conformational transitions from largely random coil structures in the absence of salt, to greater fractions of α‐helical conformations at higher NaCl concentrations, resulting in greater peptide aggregation at higher NaCl concentrations. Analysis of circular dichroism spectra also shows a similar correlation between an increase in α‐helical content and enhanced aggregation with addition of salt. Thus, the aggregation of uperin 3.5 peptides in presence of salt, results from the combined effects of electrostatic screening, enhanced interaction between hydrophobic residues, and the accompanying conformational changes that stabilize aggregate formation.

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Section: Introductionsupporting

confidence: 55%

Mechanistic insight into the early stages of amyloid formation using an anuran peptide

et al. 2019

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“…There are a numbers of inhibitors reported for the prevention of hIAPP aggregation all of which are not possible to be mentioned here, still there is a lack of rigorous research work on it . A recent study reported lysophosphatidylcholine inhibits the aggregation of human amylin through some nonspecific interactions . Nameki et al studied experimentally the effect of choline‐ O ‐sulfate on the amyloid formation of hIAPP .…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulation study on the inhibitory effects of choline‐O‐sulfate on hIAPP protofibrilation

Paul

2019

J Comput Chem

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Type 2 diabetes mellitus (T2Dm) is a neurodegenerative disease, which occurs due to the self-association of human islet amyloid polypeptide (hIAPP), also known as human amylin. It was reported experimentally that choline-O-sulfate (COS), a small organic molecule having a tertiary amino group and sulfate group, can prevent the aggregation of human amylin without providing the mechanism of the action of COS in the inhibition process. In this work, we investigate the influence of COS on the full-length hIAPP peptide by performing 500 ns classical molecular dynamics simulations. From pure water simulation (without COS), we have identified the residues 11-20 and 23-36 that mainly participate in the fibril formation, but in the presence of 1.07 M COS these residues become totally free of β-sheet conformation. Our results also show that the sulfate oxygen of COS directly interacts with the peptide backbone, which leads to the local disruption of peptide-peptide interaction. Moreover, the presence of favorable peptide-COS vdW interaction energy and high coordination number of COS molecules in the first solvation shell of the peptide indicates the hydrophobic solvation of the peptide residues by COS molecules, which also play a crucial role in the prevention of β-sheet formation. Finally, from the potential of mean force (PMFs) calculations, we observe that the free energy between two peptides is more negative in the absence of COS and with increasing concentration of COS, it becomes unfavorable significantly indicating that the peptide dimer formation is most stable in pure water, which becomes less favorable in the presence of COS.

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“…Recently, all-atom discrete molecular dynamics (DMD) simulations – a predictive and computationally efficient molecular dynamics approach [34–37] – have been used to capture the assembly dynamics of Aβ16-22 from monomers to oligomers and to fibril-like cross-β structures [38], where the formation of β-barrel oligomers was not the focus. Motivated by recent experimental and computational studies, we used the same approach to evaluate whether Aβ16-22 could also form β-barrel oligomers and to investigate the detailed structures and dynamics of these well-structured oligomers.…”

Section: Introductionmentioning

confidence: 99%

Structures and dynamics of β-barrel oligomer intermediates of amyloid-beta16-22 aggregation

Sun

Ding

2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Accumulating evidence suggests that soluble oligomers are more toxic than final fibrils of amyloid aggregations. Among the mixture of inter-converting intermediates with continuous distribution of sizes and secondary structures, oligomers in the β-barrel conformation - a common class of protein folds with a closed β-sheet - have been postulated as the toxic species with well-defined three-dimensional structures to perform pathological functions. A common mechanism for amyloid toxicity, therefore, implies that all amyloid peptides should be able to form β-barrel oligomers as the aggregation intermediates. Here, we applied all-atom discrete molecular dynamics (DMD) simulations to evaluate the formation of β-barrel oligomers and characterize their structures and dynamics in the aggregation of a seven-residue amyloid peptide, corresponding to the amyloid core of amyloid-β with a sequence of KLVFFAE (Aβ16-22). We carried out aggregation simulations with various numbers of peptides to study the size dependence of aggregation dynamics and assembly structures. Consistent with previous computational studies, we observed the formation of β-barrel oligomers in all-atom DMD simulations. Using a network-based approach to automatically identify β-barrel conformations, we systematically characterized β-barrels of various sizes. Our simulations revealed the conformational inter-conversion between β-barrels and double-layer β-sheets due to increased structural strains upon forming a closed β-barrel while maximizing backbone hydrogen bonds. The potential of mean force analysis further characterized the free energy barriers between these two states. The obtained structural and dynamic insights of β-barrel oligomers may help better understand the molecular mechanism of oligomer toxicities and design novel therapeutics targeting the toxic β-barrel oligomers. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

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Lysophosphatidylcholine modulates the aggregation of human islet amyloid polypeptide

Cited by 15 publications

References 42 publications

Mechanistic insight into the early stages of amyloid formation using an anuran peptide

Mechanistic insight into the early stages of amyloid formation using an anuran peptide

Molecular dynamics simulation study on the inhibitory effects of choline‐O‐sulfate on hIAPP protofibrilation

Structures and dynamics of β-barrel oligomer intermediates of amyloid-beta16-22 aggregation

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