Dendritic Oligoglycerol Regioisomer Mixtures and Their Utility for Membrane Protein Research

Abstract

Dendrons are an important class of macromolecules that can be used for a broad range of applications. Recent studies have indicated that mixtures of oligoglycerol detergent (OGD) regioisomers are superior to individual regioisomers for protein extraction. The origin of this phenomenon remains puzzling. Here we discuss the synthesis and characterization of dendritic oligoglycerol regioisomer mixtures and their implementation into detergents. We provide experimental benchmarks to support quality control after synthesis and investigate the unusual utility of OGD regioisomer mixtures for extracting large protein quantities from biological membranes. We anticipate that our findings will enable the development of mixed detergent platforms in the future.

Combinatorial synthesis enables scalable designer detergents for membrane protein studies

“…2B). 4,18 Mechanistically, it is anticipated that only one chlorine atom of methallyl dichloride is substituted at a time by either nucleophile a or b, and that the same applies for the formed intermediates (Fig. 2B).…”

“…18 Following this approach, a mixture of two [pG1] regioisomers (a, b) was successfully converted to a mixture of three [pG2] regioisomers (aa, ab, bb). 4,18 However, structurally similar regioisomers could not be separated by chromatography and were directly converted to a mixture of three [G2] OGD regioisomers. 4,18,19 Encouraged by the demonstration that the one-pot reaction of different nucleophiles (a, b) with methallyl dichloride leads to three different molecules (aa, ab, bb), 18 we translated this approach into a combinatorial synthesis to enable the preparation of three detergent head groups that (i) differ gradually in terms of polarity and shape, and (ii) can be separated by chromatography.…”

Supramolecular Self‐Associations of Amphiphilic Dendrons and Their Properties

“…It was shown that these dendrons can form stable proteomicelles, and can retain the activity of membrane proteins in the absence of membranes. [98] …”

Anionic Dendritic Polyglycerol for Protein Purification and Delipidation

“…8,16,17 Oligoglycerol detergents (OGDs) and their design guidelines can be used to control membrane protein purification and analysis, including protein yields, delipidation, and charge reduction, which is important for mass spectrometry. 8,17,18 Unlike detergents, the number of polymers in membrane protein research is small, and comparatively little is known about their systematic optimization. 19 Regardless of the membrane mimetic, the solubilization of membranes is the first step required to enable membrane protein purification.…”

“…A universally applicable membrane mimetic that enables membrane protein purification and is compatible with all biophysical techniques has not yet been identified. A recent breakthrough came with the demonstration that modular design principles facilitate the optimization of detergents. ,, Oligoglycerol detergents (OGDs) and their design guidelines can be used to control membrane protein purification and analysis, including protein yields, delipidation, and charge reduction, which is important for mass spectrometry. ,, Unlike detergents, the number of polymers in membrane protein research is small, and comparatively little is known about their systematic optimization …”