Melamine-cored glucosides for membrane protein solubilization and stabilization: importance of water-mediated intermolecular hydrogen bonding in detergent performance

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...

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Published in:Chemical science (Cambridge) 2023-11, Vol.14 (45), p.1314-1324
Main Authors: Ghani, Lubna, Kim, Seonghoon, Ehsan, Muhammad, Lan, Baoliang, Poulsen, Ida H, Dev, Chandra, Katsube, Satoshi, Byrne, Bernadette, Guan, Lan, Loland, Claus J, Liu, Xiangyu, Im, Wonpil, Chae, Pil Seok
Format: Article
Language:English
Subjects:
Biological activity
Chemical bonds
Detergents
Glucosides
Hydrogen
Hydrogen bonding
Hydrogen bonds
Lipids
Melamine
Membranes
Micelles
Molecular dynamics
Proteins
Solubilization
Structural stability
System effectiveness
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Summary: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. A melamine-based glucoside, MG-C11, has the ability to form a dynamic hydrogen-bonding network between detergent molecules, responsible for the markedly enhanced efficacy for GPCR stabilization compared to LMNG and previously developed TTG-C11.
ISSN:2041-6520
2041-6539
DOI:10.1039/d3sc03543c