De novo aggregation of Alzheimer’s Aβ25-35 peptides in a lipid bilayer
| Autor: | Amy K. Smith, Dmitri K. Klimov |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Dimer Lipid Bilayers lcsh:Medicine Protein aggregation Molecular Dynamics Simulation Article 03 medical and health sciences Molecular dynamics chemistry.chemical_compound Protein Aggregates Membrane biophysics 0302 clinical medicine Alzheimer Disease Humans Lipid bilayer lcsh:Science Multidisciplinary Amyloid beta-Peptides Chemistry Bilayer lcsh:R Membrane structure Energy landscape Peptide Fragments Computational biology and bioinformatics 030104 developmental biology Helix Biophysics Thermodynamics lcsh:Q Dimyristoylphosphatidylcholine Dimerization 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-12 (2019) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-43685-7 |
| Popis: | A potential mechanism of cytotoxicity attributed to Alzheimer’s Aβ peptides postulates that their aggregation disrupts membrane structure causing uncontrollable permeation of Ca2+ ions. To gain molecular insights into these processes, we have performed all-atom explicit solvent replica exchange with solute tempering molecular dynamics simulations probing aggregation of the naturally occurring Aβ fragment Aβ25-35 within the DMPC lipid bilayer. To compare the impact produced on the bilayer by Aβ25-35 oligomers and monomers, we used as a control our previous simulations, which explored binding of Aβ25-35 monomers to the same bilayer. We found that compared to monomeric species aggregation results in much deeper insertion of Aβ25-35 peptides into the bilayer hydrophobic core causing more pronounced disruption in its structure. Aβ25-35 peptides aggregate by incorporating monomer-like structures with stable C-terminal helix. As a result the Aβ25-35 dimer features unusual helix head-to-tail topology supported by a parallel off-registry interface. Such topology affords further growth of an aggregate by recruiting additional peptides. Free energy landscape reveals that inserted dimers represent the dominant equilibrium state augmented by two metastable states associated with surface bound dimers and inserted monomers. Using the free energy landscape we propose the pathway of Aβ25-35 binding, aggregation, and insertion into the lipid bilayer. |
| Databáze: | OpenAIRE |
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