Binding Mechanisms of Amyloid-like Peptides to Lipid Bilayers and Effects of Divalent Cations

Yang, Yanxing; Jalali, Sharareh; Nilsson, Bradley L.; Dias, Cristiano L.

doi:10.1021/acschemneuro.1c00140

Cited by 23 publications

(36 citation statements)

References 75 publications

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“…Amphipathic peptides with sequence that alternates strictly between non-polar (i.e., phenylalanine F) and charged amino acids (i.e., positive lysine K, and negative glutamic acid E), that is, Ac-(FKFE) 2 -NH 2 , is used to study membrane damage. Experimental studies have shown that this peptide self-assembles into amyloid fibrils forming supramolecular nanotubes. ,, In all-atom simulations, this peptide was also shown to self-assemble into amyloid-like fibrils and to interact with lipid membranes in a computationally accessible time-frame. , Here, membrane damage is studied using three anionic membranes made by combining zwitterionic, that is, 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine (POPC), 1,2-dipalmitoyl- sn -glycero-3-phosphocholine (DPPC), and 1,2-dimyristoyl- sn -glycero-3-phosphocholine (DMPC), with anionic lipids, that is, 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphoglycerol (POPG), 1,2-dipalmitoyl- sn -glycero-3-phosphoglycerol (DPPG), and 1,2-dimyristoyl- sn -glycero-3-phosphoglycerol (DMPG). The lipid composition of the three membranes studied here are 7:3 POPC/POPG, 7:3 DPPC/DPPG, and 7:3 DMPC/DMPG.…”

Section: Methodsmentioning

confidence: 99%

“…This can be explained by favorable interactions between atoms of lipid tails and nonpolar side chains. These interactions, which hold peptides anchored on the membrane surface, 60,65 also induce distortions in the lipid tail as depicted in panel m. The latter panel highlights selected lipids that are close to β-sheets before poration. Notice that acyl tails of those lipids are almost parallel to the membrane surface filling the void in the bilayer beneath β-sheets 66 and maximizing their interactions with phenylalanine side chains.…”

Section: This Quantity Is Defined Asmentioning

confidence: 99%

“…57−59 Moreover, it was shown to bind strongly to lipid bilayers. 60 Here, all-atom simulations are used to study the sequence of events accounting for the self-assembly of membrane-bound Ac-(FKFE) 2 -NH 2 peptides into β-sheets that spontaneously penetrate the membrane to form pore-like structures. The spontaneous removal of lipids from model membranes by Ac-(FKFE) 2 -NH 2 peptides are also simulated providing one of the first atomic insights into this type of membrane damage.…”

Section: ■ Introductionmentioning

confidence: 99%

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Atomic Insights into Amyloid-Induced Membrane Damage

Yang

Distaffen

Jalali

et al. 2022

ACS Chem. Neurosci.

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Amphipathic peptides can cause biological membranes to leak either by dissolving their lipid content via a detergent-like mechanism or by forming pores on the membrane surface. These modes of membrane damage have been related to the toxicity of amyloid peptides and to the activity of antimicrobial peptides. Here, we perform the first all-atom simulations in which membrane-bound amphipathic peptides self-assemble into β-sheets that subsequently either form stable pores inside the bilayer or drag lipids out of the membrane surface. An analysis of these simulations shows that the acyl tail of lipids interact strongly with non-polar side chains of peptides deposited on the membrane. These strong interactions enable lipids to be dragged out of the bilayer by oligomeric structures accounting for detergent-like damage. They also disturb the orientation of lipid tails in the vicinity of peptides. These distortions are minimized around pore structures. We also show that membrane-bound β-sheets become twisted with one of their extremities partially penetrating the lipid bilayer. This allows peptides on opposite leaflets to interact and form a long transmembrane β-sheet, which initiates poration. In simulations, where peptides are deposited on a single leaflet, the twist in β-sheets allows them to penetrate the membrane and form pores. In addition, our simulations show that fibril-like structures produce little damage to lipid membranes, as non-polar side chains in these structures are unavailable to interact with the acyl tail of lipids.

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Section: Methodsmentioning

confidence: 99%

Section: This Quantity Is Defined Asmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Atomic Insights into Amyloid-Induced Membrane Damage

Yang

Distaffen

Jalali

et al. 2022

ACS Chem. Neurosci.

Self Cite

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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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“…This is in agreement with previous work that identified electrostatic interactions to be particularly important for cationic peptides and hydrophobic peptide residues to drive the interactions of nonpolar residues with membranes. 66,116 The sequence and number of positively charged residues in peptides, such as arginine and lysine, may thus have important influence on the degree and direction in which anionic and oxidized lipids affect peptide aggregation.…”

Section: Charge At Ph 74mentioning

confidence: 99%

Lipid Oxidation Controls Peptide Self-Assembly near Membranes

John

Piantavigna

Dealey

et al. 2022

Preprint

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The self-assembly of peptides into supramolecular fibril structures has been linked to neurodegenerative diseases such as Alzheimer's disease but has also been observed in functional roles. Peptides are physiologically exposed to crowded environments of biomacromolecules, and particularly membrane lipids, within a cellular milieu. Previous research has shown that membranes can both accelerate and inhibit peptide self-assembly. Here, we studied the impact of biomimetic membranes that mimic cellular oxidative stress and compared this to mammalian and bacterial membranes. Using molecular dynamics simulations and experiments, we propose a model that explains how changes in peptide-membrane binding, electrostatics, and peptide secondary structure stabilization determine the nature of peptide self-assembly. We explored the influence of zwitterionic (POPC), anionic (POPG) and oxidized (PazePC) phospholipids, as well as cholesterol, and mixtures thereof, on the self-assembly kinetics of the amyloid β (1–40) peptide (Aβ40), linked to Alzheimer's disease, and the amyloid-forming antimicrobial peptide uperin 3.5 (U3.5). We show that the presence of an oxidized lipid had similar effects on peptide self-assembly as the bacterial mimetic membrane. While Aβ40 fibril formation was accelerated, U3.5 aggregation was inhibited by the same lipids at the same peptide-to-lipid ratio. We attribute these findings and peptide-specific effects to differences in peptide-membrane adsorption with U3.5 being more strongly bound to the membrane surface and stabilized in an α-helical conformation compared to Aβ40. Different peptide-to-lipid ratios resulted in different effects. Molecular dynamics simulations provided detailed mechanistic insights into the peptide-lipid interactions and secondary structure stability. We found that electrostatic interactions are a primary driving force for peptide-membrane interaction, enabling us to propose a model for predictions how cellular changes might impact peptide self-assembly in vivo, and potentially impact related diseases.

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Binding Mechanisms of Amyloid-like Peptides to Lipid Bilayers and Effects of Divalent Cations

Cited by 23 publications

References 75 publications

Atomic Insights into Amyloid-Induced Membrane Damage

Atomic Insights into Amyloid-Induced Membrane Damage

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

Lipid Oxidation Controls Peptide Self-Assembly near Membranes

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