De novo aggregation of Alzheimer\u2019s A\u03b225-35 peptides in a lipid bilayer

Amy K Smith,Dmitri K Klimov

doi:10.1038/s41598-019-43685-7

Abstract

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.

Highlights

Amyloid-β (Aβ) peptides are the natural products of cellular proteolysis resulting from cleavage of transmembrane amyloid precursor proteins (APP) by β and γ secretases
To gain insights into associated molecular mechanisms, we have used replica exchange with solute tempering (REST) simulations to investigate interactions of Aβ25-35 monomer with a dimyristoyl phosphatidylcholine (DMPC) lipid bilayer[34]
We discovered that the monomer binds to the membrane adopting two coexisting states: a stable state bound to the surface polar headgroups and a less stable state embedded in the hydrophobic core

Summary

Results

Aggregation does not substantially reorganize Aβ25-35 structure. We first investigated the changes in the secondary structure of Aβ25-35 peptides caused by aggregation. Amino acid positions in the bilayer analyzed above suggest different binding propensities of Aβ25-35 dimers and monomers To check this assertion, we computed the probability distributions P(Zm) of the position of the center of mass of Aβ25-35 peptide Zm along the bilayer normal. To examine changes in the bilayer structure occurring in response to Aβ25-35 dimer binding, we plot in Fig. 4 the number density nl(r, z) of DMPC heavy atoms as a function of the distance r to the peptide center of mass and the distance z to the bilayer midplane. The helical conformations in ID1 peptides predominantly occur in the C-terminal R4 region (〈H(R4)〉 = 0.60), while being sparse in the N-terminus (〈H(R3)〉 = 0.13) Due to such distribution of helical structure, Aβ25-35 peptides in a dimer are arranged in a helix head-to-tail tandem as shown in the inset to Fig. 6. The characteristics of IM are similar to those of inserted monomers I sampled in our previous REST simulations[34] (See Supplementary Information)

Discussion

Models and Methods

Additional Information