How do salt and lipids affect conformational dynamics of Aβ42 monomers in water?

Andrews, Brian; Ruggiero, Thomas; Urbanc, Brigita

doi:10.1039/d2cp05044g

Cited by 4 publications

(6 citation statements)

References 77 publications

(168 reference statements)

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“… Overall, our prior work demonstrated that CHARMM36m performs better than OPLS-AA/M and Amber ff14SB in several aspects of conformational dynamics. − Consistent with these observation, we applied CHARMM36m simulations to examine conformational ensembles of polyarginine peptides . It is also worth noting that CHARMM36m is routinely used to examine dynamics of one of the most notorious intrinsically disordered proteins, amyloid β-protein (Aβ), and its interactions with lipids , because it outperforms other MD force fields when modeling peptide self-assembly …”

Section: Resultsmentioning

confidence: 60%

“…63−66 Consistent with these observation, we applied CHARMM36m simulations to examine conformational ensembles of polyarginine peptides. 11 It is also worth noting that CHARMM36m is routinely used to examine dynamics of one of the most notorious intrinsically disordered proteins, amyloid β-protein (Aβ), and its interactions with lipids 67,68 because it outperforms other MD force fields when modeling peptide self-assembly. 69 Using the above rationale, we examined the two linear motifs using CHARMM36m/TIP3P and Amber ff14SB/TIP4P-2005 simulations (see Materials and Methods for details).…”

Section: Resultsmentioning

confidence: 99%

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Conformational Manifold Sampled by Two Short Linear Motif Segments Probed by Circular Dichroism, Vibrational, and Nuclear Magnetic Resonance Spectroscopy

Schweitzer-Stenner,

Kurbaj,

O’Neill

et al. 2023

Biochemistry

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Disordered protein segments called short linear motifs (SLiM) serve as recognition sites for a variety of biological processes and act as targeting signals, modification, and ligand binding sites. While SLiMs do not adopt one of the known regular secondary structures, the conformational distribution might still reflect the structural propensities of their amino acid residues and possible interactions between them. In the past, conformational analyses of short peptides provided compelling evidence for the notion that individual residues are less conformationally flexible than locally expected for a random coil. Here, we combined various spectroscopies (NMR, IR, vibrational, and UV circular dichroism) to determine the Ramachandran plots of two SLiM motifs, i.e., GRRDSG and GRRTSG. They are two representatives of RxxS motifs that are capable of being phosphorylated by protein kinase A, an enzyme that plays a fundamental role in a variety of biological processes. Our results reveal that the nearest and non-nearest interactions between residues cause redistributions between polyproline II and β-strand basins while concomitantly stabilizing extended relative to turn-forming and helical structures. They also cause shifts in basin positions. With increasing temperature, β-strand populations become more populated at the expense of polyproline II. While molecular dynamics simulations with Amber ff14SB and CHARMM 36m force fields indicate residue−residue interactions, they do not account for the observed structural changes.

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Section: Resultsmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Conformational Manifold Sampled by Two Short Linear Motif Segments Probed by Circular Dichroism, Vibrational, and Nuclear Magnetic Resonance Spectroscopy

Schweitzer-Stenner,

Kurbaj,

O’Neill

et al. 2023

Biochemistry

Self Cite

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show abstract

“…These time scales are far removed from those available to the computational community. The oligomeric state also affects the propensity to insert into membranes . Monomers and dimers are less likely to insert than higher oligomers.…”

Section: Discussionmentioning

confidence: 99%

“…However, this depends on the question being asked. If one aims to thoroughly characterize a well-established native state or a disordered system, , multiple shorter simulations seem preferable. However, if one wants to see if a pore collapses and this collapse takes, say, 10 μs, doing 100 simulations of 100 ns each will not be useful.…”

Section: Discussionmentioning

confidence: 99%

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Putative Pore Structures of Amyloid β 25–35 in Lipid Bilayers

Dutta,

Sepehri,

Lazaridis

2023

Biochemistry

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The amyloid β peptide aggregates to form extracellular plaques in the brains of Alzheimer's disease patients. Certain of its fragments have been found to have similar properties to those of the full-length peptide. The best-studied of these is 25-35, which aggregates into fibrils, is toxic to neurons, and forms ion channels in synthetic lipid bilayers. Here, we investigate possible pore-forming structures of oligomers of this peptide in a POPC/ POPG membrane. We consider octameric and decameric β-barrels of different topology, strand orientation, and shear, evaluate their stability in an implicit membrane model, and subject the best models to multimicrosecond all-atom molecular dynamics simulations. We find two decameric structures that are kinetically stable in membranes on this time scale: an imperfectly closed antiparallel β-barrel with K28 in the pore lumen and a short parallel β-barrel with K28 toward the membrane interface. Both structures exhibit dehydrated gaps in the pore lumen, which are larger for the antiparallel barrel. Based on these results, the experimental cation selectivity, the dependence of ion channel activity on voltage direction, and certain mutation data, the parallel model seems more compatible with experimental data.

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Survey of the Aβ-peptide structural diversity: molecular dynamics approaches

Tolstova,

Adzhubei,

Strelkova

et al. 2024

Biophys Rev

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How do salt and lipids affect conformational dynamics of Aβ42 monomers in water?

Abstract: It is well established that amyloid β-protein (Aβ) self-assembly is involved in triggering of Alzheimer’s disease. On the other hand, evidence of physiological function of Aβ interacting with lipids has...

Cited by 4 publications

References 77 publications

Conformational Manifold Sampled by Two Short Linear Motif Segments Probed by Circular Dichroism, Vibrational, and Nuclear Magnetic Resonance Spectroscopy

Conformational Manifold Sampled by Two Short Linear Motif Segments Probed by Circular Dichroism, Vibrational, and Nuclear Magnetic Resonance Spectroscopy

Putative Pore Structures of Amyloid β 25–35 in Lipid Bilayers

Survey of the Aβ-peptide structural diversity: molecular dynamics approaches

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