Throughout the in vitro studies of membrane proteins (MPs), proper detergents are essential for the preparation of stable aqueous samples. To date, universally applicable detergents have not yet been reported to accommodate the distinct requirements for the highly diversified MPs and at the different stages of MP manipulation. Detergent exchange often has to be performed. We report herein the catalytically cleavable detergents (CatCDs) that can be efficiently removed to facilitate a complete exchange. To this end, functional groups, like propargyl and allyl, are introduced as branched chains or built in the hydrophobic chain close to the hydrophilic head. The representative CatCDs can be used as usual detergents in the extraction and purification of MPs and later be removed upon the addition of catalytic palladium. Mediated by CatCD-1, reconstitution of a transporter protein MsbA into a series of detergents was achieved. The extension of these designs could facilitate the future optimization of other biophysics studies.

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.

Despite the continuous efforts, the current repertoire of detergents is still far from sufficient for the biophysics studies of membrane proteins (MPs). Toward the rapid expansion of detergent diversity, we herein report a new strategy based on Ugi reaction mediated modular assembly. Structural varieties, including hydrophobic tails and hydrophilic heads, could be conveniently introduced from the multiple reaction components. New detergents then were comprehensively evaluated in the physical properties and preliminarily screened by the thermal stabilization for a transporter MsbA and a spectrum of G protein-coupled receptors (GPCRs). For the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR, detergent M-23-M finally stood out in a second evaluation for the maintenance of homogeneity and was further illustrated its application in the improvement of NMR study. Besides the promising utility in the MP study, the current results exhibit intriguing structural-physical relationship that would allow the guidance in the tuning of detergent properties in the future.