Two‐Dimensional Detergent Expansion Strategy for Membrane Protein Studies

Abstract

Detergents are the most frequently applied reagents in membrane protein (MP) studies. The limited diversity of one‐head‐one‐tailed traditional detergents, however, is far from sufficient for structurally distinct MPs. Expansion of detergent repertoire has a continuous momentum. In line with the speculation that detergent pre‐assembly exerts superiority, herein we report for the first time cross‐conjugation of two series of monomeric detergents for constructing a two‐dimensional library of dimeric detergents. Optimum detergents stood out with unique preferences in the systematic evaluation of individual MPs. Furthermore, unprecedented hybrid detergents 14M8G and 14M9G enabled high‐quality EM study of transporter MsbA and NMR study of G protein‐coupled receptor A2AAR, respectively. Given the abundance of cross‐coupling chemistries, comprehensive diversity could be readily covered that would facilitate the finding of new detergents for the manipulation of thorny MPs and innovation of the functional and structural study in future.

Trends in the Diversification of the Detergentome

“…established further synthesis strategies to facilitate the expansion of the detergentome, i. e., two‐dimensional, clickable detergent libraries and Ugi‐mediated detergent assembly reactions, respectively (Figure 4). [27c,d] We anticipate the synthesis methods provided by Zhao et al ., [27d] Yang et al ., [27c] and Urner et al [2b] . will serve as enabling steps that transform the structural diversification and optimization of detergents for challenging future applications.…”

“…Zhao et al . developed a two‐dimensional expansion strategy to merge two monomeric detergents into hybrid detergents via copper‐catalyzed click chemistry [27d] . Following this strategy, the head groups and tails of mono‐ and disaccharide detergents, like n‐octyl‐ß‐D‐maltoside (OG) and DDM, can be readily fused into asymmetric hybrids by means of a triazole ring (Figure 10).…”

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

“…For instance, there is no plausible evidence that tripod amphiphiles (TPAs) and pre-assembled detergents (PADs) containing an amide linkage and triazole unit in the detergent core, respectively, form hydrogen bonds in a micellar or PDC state. 64,65 It is remarkable that MG-C11, a small micelle-forming detergent, is able to form intermolecular hydrogen bonding mediated by water molecules in micelle interiors. Due to their strong yet reversible nature, various bio-macromolecules such as ribonucleic acids, proteins and carbohydrates have evolved to widely utilize hydrogenbonding interactions for their individual functions.…”

Gold(I)‐Catalyzed Ring‐Closing Alkyne‐Carbonyl Metathesis for the Synthesis of Butenolides

“…The authors have cited additional references within the Supporting Information (Ref. [9][10][11][12][13][14]).…”