Atomic Insights into Amyloid-Induced Membrane Damage

Document Type

Article

Publication Date

9-21-2022

Abstract

Amphipathic peptides can cause biological membranes to leak either by dissolving their lipid content via a detergent-like mechanism or by forming pores on the membrane surface. These modes of membrane damage have been related to the toxicity of amyloid peptides and to the activity of antimicrobial peptides. Here, we perform the first all-atom simulations in which membrane-bound amphipathic peptides self-assemble into β-sheets that subsequently either form stable pores inside the bilayer or drag lipids out of the membrane surface. An analysis of these simulations shows that the acyl tail of lipids interact strongly with non-polar side chains of peptides deposited on the membrane. These strong interactions enable lipids to be dragged out of the bilayer by oligomeric structures accounting for detergent-like damage. They also disturb the orientation of lipid tails in the vicinity of peptides. These distortions are minimized around pore structures. We also show that membrane-bound β-sheets become twisted with one of their extremities partially penetrating the lipid bilayer. This allows peptides on opposite leaflets to interact and form a long transmembrane β-sheet, which initiates poration. In simulations, where peptides are deposited on a single leaflet, the twist in β-sheets allows them to penetrate the membrane and form pores. In addition, our simulations show that fibril-like structures produce little damage to lipid membranes, as non-polar side chains in these structures are unavailable to interact with the acyl tail of lipids.

Identifier

85138457635 (Scopus)

Publication Title

ACS Chemical Neuroscience

External Full Text Location

https://doi.org/10.1021/acschemneuro.2c00446

e-ISSN

19487193

PubMed ID

36095304

First Page

2766

Last Page

2777

Issue

18

Volume

13

Grant

CHE-1904364

Fund Ref

National Science Foundation

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