Dataset Information

Effect of Lauric Acid on the Stability of A?₄₂ Oligomers.

ABSTRACT: While Alzheimer's disease is correlated with the presence of A? fibrils in patient brains, the more likely agents are their precursors, soluble oligomers that may form pores or otherwise distort cell membranes. Using all-atom molecular dynamics simulation, we study how the presence of fatty acids such as lauric acid changes the stability of pore-forming oligomers built from three-stranded A?₄₂ chains. Such a change would alter the distribution of amyloids in the fatty acid-rich brain environment and therefore could explain the lower polymorphism observed in A? fibrils derived from brains of patients with Alzheimer's disease. We find that lauric acid stabilizes both ring-like and barrel-shaped models, with the effect being stronger for barrel-like models than for ring-like oligomers.

SUBMITTER: Khatua P

PROVIDER: S-EPMC7931375 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of Lauric Acid on the Stability of Aβ<sub>42</sub> Oligomers.

Khatua Prabir P Jana Asis K AK Hansmann Ulrich H E UHE

ACS omega 20210217 8

While Alzheimer's disease is correlated with the presence of Aβ fibrils in patient brains, the more likely agents are their precursors, soluble oligomers that may form pores or otherwise distort cell membranes. Using all-atom molecular dynamics simulation, we study how the presence of fatty acids such as lauric acid changes the stability of pore-forming oligomers built from three-stranded Aβ<sub>42</sub> chains. Such a change would alter the distribution of amyloids in the fatty acid-rich brain ...[more]

PMID: 33681618

Similar Datasets

Project description:Amyloid fibrils are associated with many neurodegenerative diseases. It was found that amyloidogenic oligomers, not mature fibrils, are neurotoxic agents related to these diseases. Molecular mechanisms of infectivity, pathways of aggregation, and molecular structure of these oligomers remain elusive. Here, we use all-atom molecular dynamics, molecular mechanics combined with solvation analysis by statistical-mechanical, three-dimensional molecular theory of solvation (also known as 3D-RISM-KH) in a new MM-3D-RISM-KH method to study conformational stability, and association thermodynamics of small wild-type Abeta(17-42) oligomers with different protonation states of Glu(22), as well the E22Q (Dutch) mutants. The association free energy of small beta-sheet oligomers shows near-linear trend with the dimers being thermodynamically more stable relative to the larger constructs. The linear (within statistical uncertainty) dependence of the association free energy on complex size is a consequence of the unilateral stacking of monomers in the beta-sheet oligomers. The charge reduction of the wild-type Abeta(17-42) oligomers upon protonation of the solvent-exposed Glu(22) at acidic conditions results in lowering the association free energy compared to the wild-type oligomers at neutral pH and the E22Q mutants. The neutralization of the peptides because of the E22Q mutation only marginally affects the association free energy, with the reduction of the direct electrostatic interactions mostly compensated by the unfavorable electrostatic solvation effects. For the wild-type oligomers at acidic conditions such compensation is not complete, and the electrostatic interactions, along with the gas-phase nonpolar energetic and the overall entropic effects, contribute to the lowering of the association free energy. The differences in the association thermodynamics between the wild-type Abeta(17-42) oligomers at neutral pH and the Dutch mutants, on the one hand, and the Abeta(17-42) oligomers with protonated Glu(22), on the other, may be explained by destabilization of the inter- and intrapeptide salt bridges between Asp(23) and Lys(28). Peculiarities in the conformational stability and the association thermodynamics for the different models of the Abeta(17-42) oligomers are rationalized based on the analysis of the local physical interactions and the microscopic solvation structure.

Dataset Information

Effect of Lauric Acid on the Stability of A?42 Oligomers.

Publications

Effect of Lauric Acid on the Stability of Aβ<sub>42</sub> Oligomers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Effect of Lauric Acid on the Stability of A?₄₂ Oligomers.