Binding mechanism of full-length Aβ40 peptide to a mixed lipid bilayer
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PROVIDER: S-EPMC10914957 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Nonfibrillar neurotoxic amyloid β (Aβ) oligomer structures are typically rich in β-sheets, which could be promoted by metal ions like Zn(2+). Here, using molecular dynamics (MD) simulations, we systematically examined combinations of Aβ40 peptide conformations and Zn(2+) binding modes to probe the effects of secondary structure on Aβ dimerization energies and kinetics. We found that random conformations do not contribute to dimerization either thermodynamically or kinetically. Zn(2+) couples with preformed secondary structures (α-helix and β-hairpin) to speed dimerization and stabilize the resulting dimer. Partial α-helices increase the dimerization speed, and dimers with α-helix rich conformations have the lowest energy. When Zn(2+) coordinates with residues D1, H6, H13, and H14, Aβ40 β-hairpin monomers have the fastest dimerization speed. Dimers with experimentally observed zinc coordination (E11, H6, H13, and H14) form with slower rate but have lower energy. Zn(2+) cannot stabilize fibril-like β-arch dimers. However, Zn(2+)-bound β-arch tetramers have the lowest energy. Collectively, zinc-stabilized β-hairpin oligomers could be important in the nucleation-polymerization of cross-β structures. Our results are consistent with experimental findings that α-helix to β-structural transition should accompany Aβ aggregation in the presence of zinc ions and that Zn(2+) stabilizes nonfibrillar Aβ oligomers and, thus, inhibits formation of less toxic Aβ fibrils.
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Project description:A variety of biomolecules mediate physiological processes by inserting and reorganizing in cell membranes, and the thermodynamic forces responsible for their partitioning are of great interest. Recent experiments provided valuable data on the free energy changes associated with the transfer of individual amino acids from water to membrane. However, a complete picture of the pathways and the associated changes in energy of peptide insertion into a membrane remains elusive. To this end, computational techniques supplement the experimental data with atomic-level details and shed light on the energetics of insertion. Here, we employed the technique of umbrella sampling in a total 850 ns of all-atom molecular dynamics simulations to study the free energy profile and the pathway of insertion of a model hexapeptide consisting of a tryptophan and five leucines (WL5). The computed free energy profile of the peptide as it travels from bulk solvent through the membrane core exhibits two minima: a local minimum at the water-membrane interface or the headgroup region and a global minimum at the hydrophobic-hydrophilic interface close to the lipid glycerol region. A rather small barrier of roughly 1 kcal mol (-1) exists at the membrane core, which is explained by the enhanced flexibility of the peptide when deeply inserted. Combining our results with those in the literature, we present a thermodynamic model for peptide insertion and aggregation which involves peptide aggregation upon contact with the membrane at the solvent-lipid headgroup interface.
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