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Chemistry. 2019 Sep 2;25(49):11545-11554. doi: 10.1002/chem.201902468. Epub 2019 Aug 5.

Self-Assembly Behavior and Application of Terphenyl-Cored Trimaltosides for Membrane-Protein Studies: Impact of Detergent Hydrophobic Group Geometry on Protein Stability.

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Department of Bionanotechnology, Hanyang University, Ansan, 15588, Korea.
Current address: Department of Chemistry, Mirpur University of Science & Technology, Mirpur, AJK, 10250, Pakistan).
Molecular and Cellular Physiology, Stanford, CA, 94305, USA.
Department of Neuroscience, University of Copenhagen, 2200, Copenhagen, Denmark.
Department of Cell Physiology and Molecular Biophysics, Center for Membrane Protein Research, School of Medicine, Texas Tech University Health Sciences Center Lubbock, TX, 79430, USA.
Molecular and Cellular Physiology and Structural Biology, Stanford University, Stanford, CA, 94305, USA.
Molecular Biophysics, Technische Universität Kaiserslautern (TUK), Erwin-Schrödinger-Str. 13, 67663, Kaiserslautern, Germany.
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.


Amphipathic agents are widely used in various fields including biomedical sciences. Micelle-forming detergents are particularly useful for in vitro membrane-protein characterization. As many conventional detergents are limited in their ability to stabilize membrane proteins, it is necessary to develop novel detergents to facilitate membrane-protein research. In the current study, we developed novel trimaltoside detergents with an alkyl pendant-bearing terphenyl unit as a hydrophobic group, designated terphenyl-cored maltosides (TPMs). We found that the geometry of the detergent hydrophobic group substantially impacts detergent self-assembly behavior, as well as detergent efficacy for membrane-protein stabilization. TPM-Vs, with a bent terphenyl group, were superior to the linear counterparts (TPM-Ls) at stabilizing multiple membrane proteins. The favorable protein stabilization efficacy of these bent TPMs is likely associated with a binding mode with membrane proteins distinct from conventional detergents and facial amphiphiles. When compared to n-dodecyl-β-d-maltoside (DDM), most TPMs were superior or comparable to this gold standard detergent at stabilizing membrane proteins. Notably, TPM-L3 was particularly effective at stabilizing the human β2 adrenergic receptor (β2 AR), a G-protein coupled receptor, and its complex with Gs protein. Thus, the current study not only provides novel detergent tools that are useful for membrane-protein study, but also suggests a critical role for detergent hydrophobic group geometry in governing detergent efficacy.


amphiphiles; glycolipids; membrane proteins; pi-interactions; self-assembly


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