Conformational analysis of lipid membrane mimetics modified with Aβ42 peptide by Raman spectroscopy and computer simulations

Abstract

Peptide-lipid interactions play an important role in maintaining the integrity and function of the cell membrane. Even slight changes in these interactions can induce the development of various diseases. Specifically, peptide misfolding and aggregation in the membrane is considered to be one of the triggers of Alzheimer’s disease (AD), however its exact mechanism is still unclear. To this end, an increase of amyloid-beta (Aβ) peptide concentration in the human brain is widely accepted to gradually produce cytotoxic Aβ aggregates (plaques). These plaques initiate a sequence of pathogenic events ending up in observable symptoms of dementia. Understanding the mechanism of the Aβ interaction with cells is crucial for early detection and prevention of Alzheimer’s disease. Hence, in this work, a comprehensive Raman analysis of the Aβ42 conformational dynamics in water and in liposomes and lipodiscs that mimic the membrane system is presented. The obtained results show that the secondary structure of Aβ42 in liposomes is dominated by the α–helix conformation, which remains stable over time. However, it comes as a surprise to reveal that the lipodisc environment induces the transformation of the Aβ42 secondary structure to a β-turn/random coil. Our Raman spectroscopy findings are supported with molecular dynamics (MD) and density functional theory (DFT) simulations, showing their good agreement.

Communicated by Ramaswamy H. Sarma

Keywords:

• Raman spectroscopy
• MD
• DFT
• peptide secondary structure
• conformational states

Acknowledgements

The authors have benefited from much useful access to the HybriLIT heterogeneous computing platform, kindly provided by MLIT, JINR.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

Data available on request from the authors.

Additional information

Funding

This work was supported by the JINR project ‘Nanobiophotonics’ (# 1147-1), grant for collaboration between the Joint Institute for Nuclear Research, Dubna, Russia and Serbia (JINR-Serbia_P7, 2023), and grant of the Belarusian Republican Foundation for Fundamental Research (# Т22РПМ-007).