Jan‐Simon Behnke

Non‐ionic detergents are key reagents for the characterization of membrane protein drug targets. Suitable detergents are commonly identified by trial and error, which leads to failed preparations and raising costs. Recent findings suggest that not only the chemistry of detergents but also the strategy with which detergents and proteins are brought together impact the successes of investigations. To facilitate the future development of non‐ionic detergents in membrane protein research, herein, we review chemical design concepts and detergent exchange strategies for a successful integration of detergents into the analysis of challenging membrane protein complexes. Our overview reveals exciting opportunities to tackle existing challenges, including the stabilization of G‐protein coupled receptors, the development of fluorinated detergents for studying protein–lipid binding, top‐down design of detergents, and hybrid detergents for the identification of non‐canonical lipid associations to proteins with relevance to antibiotic research. Our review will facilitate the development of chemical tools for the biophysical characterization of membrane proteins and support the discovery of biological findings in the future.

Strategies for combining ionic and non‐ionic functional groups are important for altering detergent properties and exploring new chemical spaces within the detergentome. Previous synthesis protocols for ionic/non‐ionic hybrid detergents require asymmetric detergent precursors with independently addressable hydroxyl groups that can be decorated with charged groups. However, preparation of ionic/non‐ionic headgroups can be tedious in terms of required synthesis steps and resource consumption. To address this challenge, here we explore if we can fuse ionic and non‐ionic groups directly with methallyl dichloride in the first step of detergent synthesis. While this delivers a simplified synthesis strategy for ionic/non‐ionic headgroups, we find functional groups for which the modification of asymmetric detergent precursors is still the only viable option to obtain related ionic/non‐ionic hybrid detergents. Because previously established debenzylation conditions limit overall yields for asymmetric detergent precursors, here we explore optimization strategies, including silyl protecting groups, ozonolysis‐hydrolysis, and hydrogenolysis. In summary, we establish a new synthesis route to ionic/non‐ionic hybrid detergents, deliver an optimized debenzylation protocol and obtain building blocks for bridged detergent architectures. Our findings facilitate the modular synthesis of hybrid detergents and expand the chemical space of detergents.

Ionic detergents enable applications and cause harm in biospheres due to cell toxicity. The utility of covalent combinations between ionic and non‐ionic detergent headgroups in modulating cell toxicity remains speculative due to the yet rarely explored synthesis. We close this gap and establish the modular synthesis of ionic/non‐ionic hybrid detergents. We restructure a combinatorial methallyl dichloride one‐pot coupling into a two‐step coupling, which reduces by‐products, improves product yields, and enables the gram‐scale preparation of asymmetric, cationic/non‐ionic and anionic/non‐ionic hybrid detergents. Our modular synthesis delivers new modalities for the design of ionic detergents, including an unprecedented scaling of properties that determine applications, such as charge, critical micelle concentration, solubilizing properties, hard water tolerance, and cell compatibility. We uncover that shielding the charge in ionic headgroups can switch the detergent species that is toxic to cells from monomers to mixtures of monomers and micellar assemblies. Establishing the chemistry of ionic/non‐ionic hybrid detergents provides a missing evolutionary link in the structural comparison of ionic and non‐ionic detergents, enables an easy synthesis access to yet unexplored chemical spaces of asymmetric hybrid materials, and delivers new modalities for designing the toxicity of supramolecular nanomaterials.