Melamine-cored glucosides for membrane protein solubilization and stabilization: importance of water-mediated intermolecular hydrogen bonding in detergent performance
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Membrane proteins play essential roles in a number of biological processes, and their structures are important in elucidating such processes at the molecular level and also for rational drug design and development. Membrane protein structure determination is notoriously challenging compared to that of soluble proteins, due largely to the inherent instability of their structures in non-lipid environments. Micelles formed by conventional detergents have been widely used for membrane protein manipulation, but they are suboptimal for long-term stability of membrane proteins, making downstream characterization difficult. Hence, there is an unmet need for the development of new amphipathic agents with enhanced efficacy for membrane protein stabilization. In this study, we designed and synthesized a set of glucoside amphiphiles with a melamine core, denoted melamine-cored glucosides (MGs). When evaluated with four membrane proteins (two transporters and two G protein-coupled receptors), MG-C11 conferred notably enhanced stability compared to the commonly used detergents, DDM and LMNG. These promising findings are mainly attributed to a unique feature of the MGs, i.e., the ability to form dynamic water-mediated hydrogen-bond networks between detergent molecules, as supported by molecular dynamics simulations. Thus, MG-C11 is the first example of a non-peptide amphiphile capable of forming intermolecular hydrogen bonds within a protein-detergent complex environment. Detergent micelles formed via a hydrogen-bond network could represent the next generation of highly effective membrane-mimetic systems useful for membrane protein structural studies.
Date Issued
2023-12-07
Date Acceptance
2023-10-22
Citation
Chemical Science, 2023, 14 (45), pp.13014-13024
ISSN
2041-6520
Publisher
The Royal Society of Chemistry
Start Page
13014
End Page
13024
Journal / Book Title
Chemical Science
Volume
14
Issue
45
Copyright Statement
© 2023 The Author(s). Published by the Royal Society of Chemistry. his article is licensed under aCreative Commons Attribution-NonCommercial 3.0 Unported Licence (https://creativecommons.org/licenses/by-nc/3.0/)
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/38023530
PII: d3sc03543c
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2023-10-23