- How do proteins, lipids, water, and other molecules interact in biological membranes?
- How can new, high-resolution technologies be developed and used for biomembrane research?
- How can we design drugs that modulate specific membrane functions?
Questions like these are central to the research of our three interdisciplinary teams in the Biophysics Division of the Institute of Molecular Biosciences (IMB). On the one hand, our research is driven by the curiosity to decipher complex molecular relationships within biomembranes with the aid of physical and chemical approaches and methods. On the other hand, our work aims at tackling pressing healthcare problems such as cancers with poor prognosis.
The Keller group develops native nanodiscs as versatile membrane mimetics and applies them to the biophysical investigation of membrane proteins.
The Pabst group studies the interplay between membrane proteins and lipids, paying particular attention to the asymmetric composition of plasma membranes.
The Zweytick group works on peptides derived from human immune defense proteins that selectively attack pathophysiological membranes and thus specifically target cancer cells.
Our vision is to extract membrane proteins directly from cellular membranes into so-called nanodiscs without using conventional detergents. The proteins remain in a lipid bilayer, which allows biophysical and structural studies under well-defined, yet native-like, conditions.
We pursue three main objectives:
- design and functionalization of new compounds using organic synthetic chemistry to produce nanodiscs with improved properties;
- development and application of biophysical methods to study the properties of proteins and lipids in nanodiscs;
- application of nanodiscs to answer biomolecular questions, such as exploring protein interaction networks and investigating drug targets.
Our research is focused on physical principles that pertain to the function of biological membranes with the aim to aid the development of specific membrane active compounds (peptides). For example we are studying the role of physical properties of membrane domains (rafts) in protein (ion channels, receptors) sorting and functioning, effects of the aqueous environment (pH, ion specificity, etc.), or the elastic response of membranes to peptide insertion. The approach involves a broad selection of biophysical techniques, such as small angle x-ray (neutron) scattering, calorimetry, or fluorescence microscopy to name but a few.
We work on the development of new therapies for cancer, which are derived from human host defense peptides. They act independently of cancer type and can be even used to treat cancer with poor prognosis and treatability, such as glioblastoma or malignant melanoma. Their targets are lipids specifically exposed by cancer cells. The selective peptides are optimized in model- and in vitro systems, revealing mechanism as induction of apoptosis or necrosis. To illuminate the differences between neoplastic and non-neoplastic cells as well as peptide interaction with lipids of cancer membranes diverse methods are used such as fluorescence spectroscopy and -microscopy, calorimetry, small angle x-ray scattering and others. The results gained so far enabled us to submit an international patent application for a specific set of antitumor peptides.
Aim of our research is to elucidate the molecular mode of action of antimicrobial peptides to design novel antibiotic agents that combat bacteria which are multi-resistant to conventional antibiotics. Our knowledge is fundamentally based on understanding how these peptides discriminate between host and bacteria at which lipid composition of plasma membrane plays an essential role. Thus we have been studying the interaction of natural and synthetic antimicrobial peptides with membrane mimetic systems and cell membranes using thermodynamic, spectroscopic and structural techniques. Within the framework of an EU-project coordinated by myself a world-wide patent was granted to a family of peptides derived from lactoferrin, a protein highly concentrated in human colostrum (“first milk”).