Pore Formation by Amyloid-like Peptides: Effects of the Nonpolar-Polar Sequence Pattern

Document Type

Article

Publication Date

9-18-2024

Abstract

One of the mechanisms accounting for the toxicity of amyloid peptides in diseases like Alzheimer’s and Parkinson’s is the formation of pores on the plasma membrane of neurons. Here, we perform unbiased all-atom simulations of the full membrane damaging pathway, which includes adsorption, aggregation, and perforation of the lipid bilayer accounting for pore-like structures. Simulations are performed using four peptides made with the same amino acids. Differences in the nonpolar-polar sequence pattern of these peptides prompt them to adsorb into the membrane with the extended conformations oriented either parallel [peptide labeled F1, Ac-(FKFE)2-NH2], perpendicular (F4, Ac-FFFFKKEE-NH2), or with an intermediate orientation (F2, Ac-FFKKFFEE-NH2, and F3, Ac-FFFKFEKE-NH2) in regard to the membrane surface. At the water-lipid interface, only F1 fully self-assembles into β-sheets, and F2 peptides partially fold into an α-helical structure. The β-sheets of F1 emerge as electrostatic interactions attract neighboring peptides to intermediate distances where nonpolar side chains can interact within the dry core of the bilayer. This complex interplay between electrostatic and nonpolar interactions is not observed for the other peptides. Although β-sheets of F1 peptides are mostly parallel to the membrane, some of their edges penetrate deep inside the bilayer, dragging water molecules with them. This precedes pore formation, which starts with the flow of two water layers through the membrane that expand into a stable cylindrical pore delimited by polar faces of β-sheets spanning both leaflets of the bilayer.

Identifier

85201787206 (Scopus)

Publication Title

ACS Chemical Neuroscience

External Full Text Location

https://doi.org/10.1021/acschemneuro.4c00333

e-ISSN

19487193

PubMed ID

39172951

First Page

3354

Last Page

3362

Issue

18

Volume

15

Grant

1R15GM148982-01

Fund Ref

National Research Council of Thailand

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