Division of Molekulare Biophysik

Our research activities are devoted to the molecular biophysics of membrane proteins and membrane-mimetic systems. Membrane proteins play key roles in cellular communication and transport and represent the majority of drug targets. However, these hydrophobic proteins are challenging research objects because they need to be extracted from their complex cellular membrane environment to become amenable to biophysical, structural, and functional investigations. After extraction, membrane-mimetic systems are required for reproducing the most important features of the natural membrane environment to retain the native structure and function of the target protein. We focus on the following three major lines of research.

Polymer-encapsulated lipid-bilayer nanodiscs for membrane biophysics

Detergents are traditionally used for extracting and solubilising membrane proteins. In the highly dynamic environment of a detergent micelle, however, many membrane proteins tend to denature irreversibly. Some styrene/maleic acid (SMA) copolymers enable a fundamentally new approach for investigating membrane proteins, as they obviate the use of conventional detergents. These polymers can extract proteins and surrounding lipids directly from cellular membranes to form nanosized discs, where the polymer wraps around a lipid-bilayer patch.

We have recently discovered that a copolymer named diisobutylene/maleic acid (DIBMA) is equally capable of accommodating membrane proteins and lipids in native nanodiscs, thus rendering them amenable to biophysical, structural, and functional scrutiny. The major advantage of this new polymer lies in the fact that it is compatible with optical spectroscopy in the ultraviolet range, does not disturb the order, dynamics, and hydration of the extracted membrane fragment, and tolerates elevated concentrations of metal ions often required for membrane-protein activity.

Chem. Phys. Lipids 2019, 221, 30; Eur. Polym. J. 201810, 206; J. Membr. Biol. 2018, 251, 443; Langmuir 2017, 33, 14378; Sci. Rep. 2017, 7, 11517;  Sci. Rep. 2017, 7, 45875; Angew. Chem. Int. Ed. 201756, 1919; Nanoscale 2016, 8, 15016; Nanoscale 20157, 20685

Self-assembling fluorinated amphiphiles as mild membrane mimics

A different approach towards engineering mild membrane mimics relies on fluorinated amphiphiles. Owing to the weak affinity of fluorocarbons for hydrocarbons and to the larger volume of the former, such fluorosurfactants are less destabilising because they do not compete with native protein/protein and protein/lipid interactions. For the same reason, however, fluorosurfactants are thought to be unable to extract proteins directly from biological membranes.

We have found that the poor miscibility of fluorocarbons and hydrocarbons at the macroscale need not apply at the nanoscale. We now exploit this discovery to develop fluorosurfactants that display favourable physicochemical properties such as small and well-defined micelles, partition into, translocate across, and solubilise membranes in a rapid, thermodynamically controlled manner, extract proteins directly from cellular membranes, and provide these proteins with a stabilising membrane-mimetic environment that preserves their native structures and functions.

Methods 2018, 147, 84; Anal. Chem. 2017, 89, 3245; New J. Chem 2016, 40, 5364; Nanoscale 20157, 20685; Angew. Chem. Int. Ed. 2015, 54, 5069; J. Colloid Interface Sci. 2015, 445, 127

The third line of research focusses on the interactions of proteins with small-molecule ligands, lipid membranes, and other proteins. To this end, we combine the new membrane mimics developed in the above-mentioned projects with spectroscopic, scattering, chromatographic, calorimetric, and other methods as well as model building to elucidate the structures, dynamics, and functions of membrane proteins.

We currently focus our efforts on G-protein-coupled receptors (GPCRs), ligand-gated ion channels, and pore-forming proteins, all of which are of great physiological and therapeutic relevance. Moreover, we continuously develop and improve methods and protocols for rendering these proteins accessible to in vitro investigations in a native-like yet nanoscale lipid-bilayer environment.

Curr. Opin. Struct. Biol. 2019, 58,124; ACS Omega 2018, 3, 12026; Commun. Biol. 2018, 154, 1; J. Phys. Chem. Lett. 2018, 9, 2241; J. Mol. Biol. 2018, 430, 554;  Biophys. J. 2017, 113, 1280; Nat. Protoc. 2016, 11, 882; Biol. Proced. Online 2016, 18, 4; Methods Enzymol. 2016, 567, 129; Anal. Chem. 2015, 87, 11224

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