Binding Mechanisms of Amyloid-like Peptides to Lipid Bilayers and Effects of Divalent Cations

Document Type

Article

Publication Date

6-2-2021

Abstract

In several neurodegenerative diseases, cell toxicity can emerge from damage produced by amyloid aggregates to lipid membranes. The details accounting for this damage are poorly understood including how individual amyloid peptides interact with phospholipid membranes before aggregation. Here, we use all-atom molecular dynamics simulations to investigate the molecular mechanisms accounting for amyloid-membrane interactions and the role played by calcium ions in this interaction. Model peptides known to self-assemble into amyloid fibrils and bilayer made from zwitterionic and anionic lipids are used in this study. We find that both electrostatic and hydrophobic interactions contribute to peptide-bilayer binding. In particular, the attraction of peptides to lipid bilayers is dominated by electrostatic interactions between positive residues and negative phosphate moieties of lipid head groups. This attraction is stronger for anionic bilayers than for zwitterionic ones. Hydrophobicity drives the burial of nonpolar residues into the interior of the bilayer producing strong binding in our simulations. Moreover, we observe that the attraction of peptides to the bilayer is significantly reduced in the presence of calcium ions. This is due to the binding of calcium ions to negative phosphate moieties of lipid head groups, which leaves phospholipid bilayers with a net positive charge. Strong binding of the peptide to the membrane occurs less frequently in the presence of calcium ions and involves the formation of a "Ca2+ bridge".

Identifier

85106388121 (Scopus)

Publication Title

ACS Chemical Neuroscience

External Full Text Location

https://doi.org/10.1021/acschemneuro.1c00140

e-ISSN

19487193

PubMed ID

33973758

First Page

2027

Last Page

2035

Issue

11

Volume

12

Grant

ACI-1548562

Fund Ref

National Science Foundation

This document is currently not available here.

Share

COinS