Molecular Simulations of Amyloid Structures, Toxicity, and Inhibition

Zhang, Mingzhen; Ren, Baiping; Chen, Hong; Sun, Yan; Ma, Jie; Jiang, Binbo; Zheng, Jie

doi:10.1002/ijch.201600075

Cited by 29 publications

(19 citation statements)

References 154 publications

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“…The AMF images of Aβ barrel-like structures revealed an outer diameter of 8–12 nm and an inner diameter of the cavity pore as 1–2 nm [57]. Computational studies about the polymorphism of Aβ barrel-like structures had also been carried out and revealed the linkage of Aβ barrels and amyloid channels in cell membranes [58, 59]. Moreover, the comparison of modeled channels of different amyloid peptides showed shared structural features, suggesting the formation of β-barrel structure is generic mechanism inducing toxicity among amyloid peptides.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…The characterization of a monomeric form of hIAPP in solution and its molecular mechanism of aggregation are important to understand its cellular toxicity and role in T2D . This could be instrumental for the design of inhibitors that have the ability to slow down hIAPP aggregation or redirect it to a pathway which results in nontoxic aggregates and may present a new therapeutic strategy for the treatment of T2D.…”

Section: Introductionmentioning

confidence: 99%

Targeting Human Islet Amyloid Polypeptide Aggregation and Toxicity in Type 2 Diabetes: An Overview of Peptide-Based Inhibitors

Saini

Goyal

2020

Chem. Res. Toxicol.

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Type 2 diabetes (T2D) is a chronic metabolic disease characterized by insulin resistance and a progressive loss of pancreatic islet β-cell mass, which leads to insufficient secretion of insulin and hyperglycemia. Emerging evidence suggests that toxic oligomers and fibrils of human islet amyloid polypeptide (hIAPP) contribute to the death of β-cells and lead to T2D pathogenesis. These observations have opened new avenues for the development of islet amyloid therapies for the treatment of T2D. The peptidebased inhibitors are of great value as therapeutic agents against hIAPP aggregation in T2D owing to their biocompatibility, feasibility of synthesis and modification, high specificity, low toxicity, proteolytic stability (modified peptides), and weak immunogenicity as well as the large size of involved interfaces during self-aggregation of hIAPP. An understanding of what has been done and achieved will provide key insights into T2D pathology and assist in the discovery of more potent drug candidates for the treatment of T2D. In this article, we review various peptide-based inhibitors of hIAPP aggregation, including those derived from the hIAPP sequence and those not based on the sequence, consisting of both natural as well as unnatural amino acids and their derivatives. The present review will be beneficial in advancing the field of peptide medicine for the treatment of T2D.

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“…Upon enrichment of membrane-adsorbed peptides and subsequent formation of toxic oligomers, hIAPPs cooperatively transform into β-sheet aggregates [17–19]. Membrane-bound hIAPP oligomers not only promote amyloid formation but also induce membrane leakage [20–22]. However, it remains challenging to experimentally detect how hIAPP oligomers interact with membranes.…”

Section: Introductionmentioning

confidence: 99%

Atomistic-level study of the interactions between hIAPP protofibrils and membranes: Influence of pH and lipid composition

Qian

Zou

Zhang

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The pathology of type 2 diabetes mellitus is associated with the aggregation of human islet amyloid polypeptide (hIAPP) and aggregation-mediated membrane disruption. The interactions of hIAPP aggregates with lipid membrane, as well as the effects of pH and lipid composition at the atomic level, remain elusive. Herein, using molecular dynamics simulations, we investigate the interactions of hIAPP protofibrillar oligomers with lipids, and the membrane perturbation that they induce, when they are partially inserted in an anionic dipalmitoyl-phosphatidylglycerol (DPPG) membrane or a mixed dipalmitoyl-phosphatidylcholine (DPPC)/DPPG (7:3) lipid bilayer under acidic/neutral pH conditions. We observed that the tilt angles and insertion depths of the hIAPP protofibril are strongly correlated with the pH and lipid composition. At neutral pH, the tilt angle and insertion depth of hIAPP protofibrils at a DPPG bilayer reach ~52° and ~1.62 nm with respect to the membrane surface, while they become ~77° and ~1.75 nm at a mixed DPPC/DPPG membrane. The calculated tilt angle of hIAPP at DPPG membrane is consistent with a recent chiral sum frequency generation spectroscopic study. The acidic pH induces a smaller tilt angle of ~40° and a shallower insertion depth (~1.24 nm) of hIAPP at the DPPG membrane surface, mainly due to protonation of His18 near the turn region. These differences mainly result from a combination of distinct electrostatic, van der Waals, hydrogen bonding and salt-bridge interactions between hIAPP and lipid bilayers. The hIAPP-membrane interaction energy analysis reveals that besides charged residues K1, R11 and H18, aromatic residues Phe15 and Phe23 also exhibit strong interactions with lipid bilayers, revealing the crucial role of aromatic residues in stabilizing the membrane-bound hIAPP protofibrils. hIAPP-membrane interactions disturb the lipid ordering and the local bilayer thickness around the peptides. Our results provide atomic-level information of membrane interaction of hIAPP protofibrils, revealing pH-dependent and membrane-modulated hIAPP aggregation at the early stage.

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Molecular Simulations of Amyloid Structures, Toxicity, and Inhibition

Cited by 29 publications

References 154 publications

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

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

Targeting Human Islet Amyloid Polypeptide Aggregation and Toxicity in Type 2 Diabetes: An Overview of Peptide-Based Inhibitors

Atomistic-level study of the interactions between hIAPP protofibrils and membranes: Influence of pH and lipid composition

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