Dataset Information

A coarse-grained molecular dynamics investigation on spontaneous binding of Aβ_1-40 fibrils with cholesterol-mixed DPPC bilayers.

ABSTRACT: Alzheimer's disease is the most common form of dementia. Its aetiology is characterized by the misfolding and aggregation of amyloid-β (Aβ) peptides into β-sheet-rich Aβ oligomers/fibrils. Although multiple experimental studies have suggested that Aβ oligomers/fibrils interact with the cell membranes and perturb their structures and dynamics, the molecular mechanism of this interaction is still not fully understood. In the present work, we have performed a total of 120 μs-long simulations to investigate the interaction between trimeric or hexameric Aβ_1-40 fibrils with either a 100% DPPC bilayer, a 70% DPPC-30% cholesterol bilayer or a 50% DPPC-50% cholesterol bilayer. Our simulation data capture the spontaneous binding of the aqueous Aβ_1-40 fibrils with the membranes and show that the central hydrophobic amino acid cluster, the lysine residue adjacent to it and the C-terminal hydrophobic residues are all involved in the process. Moreover, our data show that while the Aβ_1-40 fibril does not bind to the 100% DPPC bilayer, its binding affinity for the membrane increases with the amount of cholesterol. Overall, our data suggest that two clusters of hydrophobic residues and one lysine help Aβ_1-40 fibrils establish stable interactions with a cholesterol-rich DPPC bilayer. These residues are likely to represent potential target regions for the design of inhibitors, thus opening new avenues in structure-based drug design against Aβ oligomer/fibril-membrane interaction.

SUBMITTER: Agrawal N

PROVIDER: S-EPMC10151222 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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A coarse-grained molecular dynamics investigation on spontaneous binding of Aβ<sub>1-40</sub> fibrils with cholesterol-mixed DPPC bilayers.

Agrawal Nikhil N Skelton Adam A AA Parisini Emilio E

Computational and structural biotechnology journal 20230415

Alzheimer's disease is the most common form of dementia. Its aetiology is characterized by the misfolding and aggregation of amyloid-β (Aβ) peptides into β-sheet-rich Aβ oligomers/fibrils. Although multiple experimental studies have suggested that Aβ oligomers/fibrils interact with the cell membranes and perturb their structures and dynamics, the molecular mechanism of this interaction is still not fully understood. In the present work, we have performed a total of 120 μs-long simulations to inv ...[more]

PMID: 37143763

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Project description:Cholesterol trafficking, which is an essential function in mammalian cells, is intimately connected to molecular-scale interactions through cholesterol modulation of membrane structure and dynamics and interaction with membrane receptors. Since these effects of cholesterol occur on micro- to millisecond timescales, it is essential to develop accurate coarse-grained simulation models that can reach these timescales. Cholesterol has been shown experimentally to thicken the membrane and increase phospholipid tail order between 0-40% cholesterol, above which these effects plateau or slightly decrease. Here, we showed that the published MARTINI coarse-grained force-field for phospholipid (POPC) and cholesterol fails to capture these effects. Using reference atomistic simulations, we systematically modified POPC and cholesterol bonded parameters in MARTINI to improve its performance. We showed that the corrections to pseudo-bond angles between glycerol and the lipid tails and around the oleoyl double bond particle (the "angle-corrected model") slightly improves the agreement of MARTINI with experimentally measured thermal, elastic, and dynamic properties of POPC membranes. The angle-corrected model improves prediction of the thickening and ordering effects up to 40% cholesterol but overestimates these effects at higher cholesterol concentration. In accordance with prior work that showed the cholesterol rough face methyl groups are important for limiting cholesterol self-association, we revised the coarse-grained representation of these methyl groups to better match cholesterol-cholesterol radial distribution functions from atomistic simulations. In addition, by using a finer-grained representation of the branched cholesterol tail than MARTINI, we improved predictions of lipid tail order and bilayer thickness across a wide range of concentrations. Finally, transferability testing shows that a model incorporating our revised parameters into DOPC outperforms other CG models in a DOPC/cholesterol simulation series, which further argues for its efficacy and generalizability. These results argue for the importance of systematic optimization for coarse-graining biologically important molecules like cholesterol with complicated molecular structure.

Dataset Information

A coarse-grained molecular dynamics investigation on spontaneous binding of Aβ_1-40 fibrils with cholesterol-mixed DPPC bilayers.

Publications

A coarse-grained molecular dynamics investigation on spontaneous binding of Aβ<sub>1-40</sub> fibrils with cholesterol-mixed DPPC bilayers.

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Dataset Information

A coarse-grained molecular dynamics investigation on spontaneous binding of Aβ1-40 fibrils with cholesterol-mixed DPPC bilayers.

Publications

A coarse-grained molecular dynamics investigation on spontaneous binding of Aβ<sub>1-40</sub> fibrils with cholesterol-mixed DPPC bilayers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

A coarse-grained molecular dynamics investigation on spontaneous binding of Aβ_1-40 fibrils with cholesterol-mixed DPPC bilayers.