Probing the Structure of Toxic Amyloid-β Oligomers with Electron Spin Resonance and Molecular Modeling

Banchelli, Martina; Cascella, Roberta; D’Andrea, Cristiano; Penna, Giovanni La; Li, Mai Suan; Machetti, Fabrizio; Matteini, Paolo; Pizzanelli, Silvia

doi:10.1021/acschemneuro.0c00714

Cited by 11 publications

(16 citation statements)

References 99 publications

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“…This phenomenon is affected by specific lipids including cholesterol, sphingomyelin, and gangliosides [717,718]: lipid types typically present in the outer leaflet of the cell membrane. Amyloid fibers at a membrane surface have thus been frequently studied using MD simulations, e.g., [719][720][721][722][723][724][725][726][727][728][729][730], however, a surprisingly small fraction of this work has been performed in the context of drug design [731,732]. Khondker et al, proposed designing drugs with a mode of action that involved modulating membrane properties to affect the aggregation of amyloid-β25-35 at the bilayer surface [229].…”

Section: Can Drugs Prevent Amyloid Formation Via the Modification Of Membrane Properties?mentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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Section: Can Drugs Prevent Amyloid Formation Via the Modification Of Membrane Properties?mentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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“… 29 Recent experiments have also shown that cell toxicity is associated with nanoparticles of about 4 nm in height. 30 Such nanoparticles fit with annular assemblies of three tetramers or dodecamers. For comparison with the dodecamer, we used a model of mature fibrils which have 12 Aβ42 chains.…”

Section: Introductionmentioning

confidence: 99%

Amyloid β Dodecamer Disrupts the Neuronal Membrane More Strongly than the Mature Fibril: Understanding the Role of Oligomers in Neurotoxicity

et al. 2022

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The amyloid cascade hypothesis states that senile plaques, composed of amyloid β (Aβ) fibrils, play a key role in Alzheimer’s disease (AD). However, recent experiments have shown that Aβ oligomers are more toxic to neurons than highly ordered fibrils. The molecular mechanism underlying this observation remains largely unknown. One of the possible scenarios for neurotoxicity is that Aβ peptides create pores in the lipid membrane that allow Ca 2+ ions to enter cells, resulting in a signal of cell apoptosis. Hence, one might think that oligomers are more toxic due to their higher ability to create ion channels than fibrils. In this work, we study the effect of Aβ42 dodecamer and fibrils on a neuronal membrane, which is similar to that observed in AD patients, using all-atom molecular dynamics simulations. Due to short simulation times, we cannot observe the formation of pores, but useful insight on the early events of this process has been obtained. Namely, we showed that dodecamer distorts the lipid membrane to a greater extent than fibrils, which may indicate that ion channels can be more easily formed in the presence of oligomers. Based on this result, we anticipate that oligomers are more toxic than mature fibrils, as observed experimentally. Moreover, the Aβ–membrane interaction was found to be governed by the repulsive electrostatic interaction between Aβ and the ganglioside GM1 lipid. We calculated the bending and compressibility modulus of the membrane in the absence of Aβ and obtained good agreement with the experiment. We predict that the dodecamer will increase the compressibility modulus but has little effect on the bending modulus. Due to the weak interaction with the membrane, fibrils insignificantly change the membrane elastic properties.

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“…In both, the S1 and S2 segments comprise a parallel β‐sheet with a bend near the center of S1. Banchelli et al 42 found that Cu ++ causes formation of dimers by binding between His6 and His13 or His14 of two Aβ monomers. They concluded that at least portions of adjacent S1 segments are antiparallel (consistent with some of our models) rather than in‐register parallel.…”

Section: Introductionmentioning

confidence: 99%

The amyloid concentric β‐barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils

Durell

Kayed

H³

2022

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Amyloid beta (Aβ) peptides are a major contributor to Alzheimer's disease. They occur in differing lengths, each of which forms a multitude of assembly types. The most toxic soluble oligomers are formed by Aβ42; some of which have antiparallel β‐sheets. Previously, our group proposed molecular models of Aβ42 hexamers in which the C‐terminus third of the peptide (S3) forms an antiparallel 6‐stranded β‐barrel that is surrounded by an antiparallel barrel formed by the more polar N‐terminus (S1) and middle (S2) portions. These hexamers were proposed to act as seeds from which dodecamers, octadecamers, both smooth annular protofibrils (sAPFs) and beaded annular protofibrils (bAPFs), and transmembrane channels form. Since then, numerous aspects of our models have been supported by experimental findings. Recently, NMR‐based structures have been proposed for Aβ42 tetramers and octamers, and NMR studies have been reported for oligomers composed of ~32 monomers. Here we propose a range of concentric β‐barrel models and compare their dimensions to image‐averaged electron micrographs of both bAPFs and sAPFs of Aβ42. The smaller oligomers have 6, 8, 12, 16, and 18 monomers. These beads string together to form necklace‐like bAPFs. These bAPRs gradually morph into sAPFs in which a S3 β‐barrel is shielded on one or both sides by β‐barrels formed from S1 and S2 segments.

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Probing the Structure of Toxic Amyloid-β Oligomers with Electron Spin Resonance and Molecular Modeling

Cited by 11 publications

References 99 publications

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Amyloid β Dodecamer Disrupts the Neuronal Membrane More Strongly than the Mature Fibril: Understanding the Role of Oligomers in Neurotoxicity

The amyloid concentric β‐barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils

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