Binding of Aβ peptide creates lipid density depression in DMPC bilayer

Lockhart, Christopher; Klimov, Dmitri K.

doi:10.1016/j.bbamem.2014.07.010

Cited by 23 publications

(67 citation statements)

References 43 publications

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“…The amino-truncated A β 10–40 monomer was chosen as a proxy to full-length A β 1–40. Our previous simulations 29,30 have indicated that this peptide reproduces several A β 1–40 experimental observations, including the distribution of helical structure along the sequence and partial insertion of A β in the bilayer 12,31,32 . Additionally, A β 10–40 peptides are naturally occurring cytotoxic and amyloidogenic species 33–36 .…”

Section: Methodssupporting

confidence: 64%

“…The contribution of all restraints to the potential energy at 330 K is minor (≈0.6 kcal/mol RT ). Moreover, our previous studies have shown that the effect of restraints on lipid structural properties is generally within the sampling error 30,45 . Because we detected no instances of interpeptide interactions via amino acid side chain contacts or cross-bridges by a third molecule, we assume that the peptides bind to the bilayer independently as monomers.…”

Section: Methodsmentioning

confidence: 91%

“…Additionally, A β 10–40 peptides are naturally occurring cytotoxic and amyloidogenic species 33–36 . The DMPC bilayer was chosen because it is well characterized experimentally affording direct comparisons with simulation data 30 and the binding of WT A β 10–40 to DMPC bilayer approximately reproduces experimental observations for SDS micelles 12,31 .

Figure 1( a ) Sequence of A β 10–40 peptide with highlighted regions R1–R4. ( b ) Oxidation of hydrophobic methionine side chain results in polar methionine sulfoxide.…”

Section: Methodsmentioning

confidence: 92%

“…One-dimensional number densities for lipid, peptide, and water atoms were obtained in a similar way. Ordering in lipid fatty acid tails was quantified by the lipid carbon-deuterium order parameter S CD and tail tilts γ computed for sn − 2 chains 30 .…”

Section: Methodsmentioning

confidence: 99%

“…To bridge this gap, we performed isobaric-isothermal all-atom replica exchange molecular dynamics simulations with solute tempering (REST) 28 to probe the binding of oxidized A β peptides to the DMPC bilayer. As a control, we utilized our previous studies, which probed binding of WT A β peptides to the same bilayer 29,30 . Below we present our analysis, which delineates the MetO binding mechanism and distinguishes it from that governing WT binding.…”

Section: Introductionmentioning

confidence: 99%

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Methionine Oxidation Changes the Mechanism of Aβ Peptide Binding to the DMPC Bilayer

Lockhart

Smith

Klimov

2019

Sci Rep

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Using all-atom explicit solvent replica exchange molecular dynamics simulations with solute tempering, we study the effect of methionine oxidation on A β 10–40 peptide binding to the zwitterionic DMPC bilayer. By comparing oxidized and reduced peptides, we identified changes in the binding mechanism caused by this modification. First, Met35 oxidation unravels C-terminal helix in the bound peptides. Second, oxidation destabilizes intrapeptide interactions and expands bound peptides. We explain these outcomes by the loss of amphiphilic character of the C-terminal helix due to oxidation. Third, oxidation “polarizes” A β binding to the DMPC bilayer by strengthening the interactions of the C-terminus with lipids while largely releasing the rest of the peptide from bilayer. Fourth, in contrast to the wild-type peptide, oxidized A β induces significantly smaller bilayer thinning and drop in lipid density within the binding footprint. These observations are the consequence of mixing oxidized peptide amino acids with lipids promoted by enhanced A β conformational fluctuations. Fifth, methionine oxidation reduces the affinity of A β binding to the DMPC bilayer by disrupting favorable intrapeptide interactions upon binding, which offset the gains from better hydration. Reduced binding affinity of the oxidized A β may represent the molecular basis for its reduced cytotoxicity.

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Section: Methodssupporting

confidence: 64%

Section: Methodsmentioning

confidence: 91%

Figure 1( a ) Sequence of A β 10–40 peptide with highlighted regions R1–R4. ( b ) Oxidation of hydrophobic methionine side chain results in polar methionine sulfoxide.…”

Section: Methodsmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Methionine Oxidation Changes the Mechanism of Aβ Peptide Binding to the DMPC Bilayer

Lockhart

Smith

Klimov

2019

Sci Rep

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Label‐free, chronological and selective detection of aggregation and fibrillization of amyloid β protein in serum by microcantilever sensor immobilizing cholesterol‐incorporated liposome

Taniguchi

Shimanouchi

Sohgawa

et al. 2020

Biotech & Bioengineering

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To facilitate the early diagnosis of Alzheimer's disease and mild cognitive impairment patients, we developed a cantilever‐based microsensor that immobilized liposomes of various phospholipids to detect a trace amount of amyloid β (Aβ) protein, and investigated its aggregation and fibrillization on model cell membranes in human serum. Three species of liposomes composed of different phospholipids of 1,2‐dipalmtoyl‐sn‐glycero‐3‐phosphocholine (DPPC), DPPC/phosphatidyl ethanolamine and 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphorylglycerol having varied hydrophilic groups were applied, which showed different chronological interactions with Aβ(1–40) protein and varied sensitivities of the cantilever sensor, depending on their specific electrostatic charged conditions, hydrophilicity, and membrane fluidity. 1,2‐dimyristoyl‐sn‐glycero‐3‐phosphocholine (DMPC) having short hydrophobic carbon chains confirmed to show a large interaction with Aβ(1–40) and a high sensitivity. Furthermore, the incorporation of cholesterol into DMPC was effective to selectively detect Aβ(1–40) in human serum, which effect was also checked by quartz crystal microbalance. Finally, Aβ detection of 100‐pM order was expected selectively in the serum by using the developed biosensor.

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Calcium inhibits penetration of Alzheimer's Aβ₁–₄₂ monomers into the membrane

Boopathi

Garduño‐Juárez

2022

Proteins

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Calcium ion regulation plays a crucial role in maintaining neuronal functions such as neurotransmitter release and synaptic plasticity. Copper (Cu2+) coordination to amyloid‐β (Aβ) has accelerated Aβ1–42 aggregation that can trigger calcium dysregulation by enhancing the influx of calcium ions by extensive perturbing integrity of the membranes. Aβ1–42 aggregation, calcium dysregulation, and membrane damage are Alzheimer disease (AD) implications. To gain a detail of calcium ions' role in the full‐length Aβ1–42 and Aβ1‐42‐Cu2+ monomers contact, the cellular membrane before their aggregation to elucidate the neurotoxicity mechanism, we carried out 2.5 μs extensive molecular dynamics simulation (MD) to rigorous explorations of the intriguing feature of the Aβ1–42 and Aβ1–42‐Cu2+ interaction with the dimyristoylphosphatidylcholine (DMPC) bilayer in the presence of calcium ions. The outcome of the results compared to the same simulations without calcium ions. We surprisingly noted robust binding energies between the Aβ1–42 and membrane observed in simulations containing without calcium ions and is two and a half fold lesser in the simulation with calcium ions. Therefore, in the case of the absence of calcium ions, N‐terminal residues of Aβ1–42 deeply penetrate from the surface to the center of the bilayer; in contrast to calcium ions presence, the N‐ and C‐terminal residues are involved only in surface contacts through binding phosphate moieties. On the other hand, Aβ1–42‐Cu2+ actively participated in surface bilayer contacts in the absence of calcium ions. These contacts are prevented by forming a calcium bridge between Aβ1–42‐Cu2+ and the DMPC bilayer in the case of calcium ions presence. In a nutshell, Calcium ions do not allow Aβ1–42 penetration into the membranes nor contact of Aβ1–42‐Cu2+ with the membranes. These pieces of information imply that the calcium ions mediate the membrane perturbation via the monomer interactions but do not damage the membrane; they agree with the western blot experimental results of a higher concentration of calcium ions inhibit the membrane pore formation by Aβ peptides.

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Binding of Aβ peptide creates lipid density depression in DMPC bilayer

Cited by 23 publications

References 43 publications

Methionine Oxidation Changes the Mechanism of Aβ Peptide Binding to the DMPC Bilayer

Methionine Oxidation Changes the Mechanism of Aβ Peptide Binding to the DMPC Bilayer

Label‐free, chronological and selective detection of aggregation and fibrillization of amyloid β protein in serum by microcantilever sensor immobilizing cholesterol‐incorporated liposome

Calcium inhibits penetration of Alzheimer's Aβ₁–₄₂ monomers into the membrane

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Binding of Aβ peptide creates lipid density depression in DMPC bilayer

Cited by 23 publications

References 43 publications

Methionine Oxidation Changes the Mechanism of Aβ Peptide Binding to the DMPC Bilayer

Methionine Oxidation Changes the Mechanism of Aβ Peptide Binding to the DMPC Bilayer

Label‐free, chronological and selective detection of aggregation and fibrillization of amyloid β protein in serum by microcantilever sensor immobilizing cholesterol‐incorporated liposome

Calcium inhibits penetration of Alzheimer's Aβ1–42 monomers into the membrane

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Calcium inhibits penetration of Alzheimer's Aβ₁–₄₂ monomers into the membrane