Research in the Theoretical Molecular Biophysics group is focused on advancing our understanding of the molecular mechanisms by which important proteins carry out their biological function. Our studies involve both individual proteins and larger macromolecular assemblies, and the type of processes we investigate range from ligand binding to conformational change. Our research approach involves physics-based, computationally-intensive molecular simulations and other theoretical methods. Through these we analyze the structure, dynamics and energetics of the molecular systems under study, which enable us to formulate novel mechanistic hypothesis or interpretations of the exising data.
Our theoretical work is often carried out in close collaboration with experimentalists, particularly in the areas of structural biology, biochemistry and molecular biophysics. The Riedberg Campus in Frankfurt am Main provides a highly interdisciplinary, international environment from which we benefit greatly - in addition to our interactions with groups located elsewhere in Europe and abroad. The following is a brief description of our research interests.
Mechanisms of energy conversion in membrane transporters and enzymes
Proteins embedded in or associated with biological membranes are of essential importance; they mediate a wide range of processes such as the communication between and within cells, the import and metabolism of nutrients, etc. They have also great potential for biotechnological applications and as pharmaceutical targets. We are interested in the class of membrane proteins whose function is coupled to electrochemical gradients across the membranes where they reside. Our research attempts to elucidate the structural mechanisms that enable these proteins to employ such gradients in order to drive their function - or conversely, the mechanisms by which they create electrochemical gradients driven by other energy sources, such as light, chemical reactions, etc.
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A paradigmatic example of this class of membrane-associated proteins is the ATP synthase. These enzymes produce ATP through a rotary mechanism that is driven by the downhill diffusion of protons (and sometimes sodium) across the protein membrane subunits. However, they become ion pumps when they catalyze ATP hydrolysis, thereby inverting the rotary mechanism. We are actively pursuing several research projects in this area, aimed at understanding the structural and physico-chemical basis of this fascinating mechanism of energy conversion. The image portrays a molecular-simulation model of the so-called membrane rotor.
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Mechanisms of recognition and signaling at the immunological synapse
Designated cells in our adaptive immune system are able to display on their surface protein fragments or lipids belonging to foreign organisms, such as bacteria or viruses. These foreign antigens can be then recognized by special lymphocytes called T-cells; the transient interface formed between an antigen-presenting cell and a T-cell is known as the immunological synapse. Upon recognition of foreign antigens, a chemical signal is generated at the membrane of the T-cell and transmitted towards its interior. These activating signals ultimately translate into diverse biochemical responses that protect us from infection.
A great diversity of proteins contribute to the formation of the immunological synapse and the subsequent signaling process. These include antigen-binding proteins, membrane receptors, scaffolding proteins, tyrosine kinases, and even ion channels. The immunological synapse thus encompasses many of the processes mediated by proteins in all forms of life, from substrate recognition to allostery and conformation change to membrane permeation. This area is therefore an important focus of our research.
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Self-organization and conformational regulation in modular protein domains
The transmission of information within cells requires the organization of a diverse range of proteins into coherent interaction networks. Spatially, this requires the transient formation of macromolecular complexes, so as to allow the relay of chemical signals from protein to protein. So-called modular protein domains play a fundamental role in the dynamic scaffolding of these signaling complexes. These small modules can act as promoters or inhibitors of the interaction between protein partners within a network, thus regulating the transduction of signals. A good overview of the structure and function of these modules can be found for example following this link.
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The versatility of modular domains is in part conferred by their own ability to self-organize into multi-modular constructs, which may adopt alternate arrangements with distinct binding properties. Furthermore, individual modular domains can also adopt multiple conformations in response to environmental stimuli. Both these aspects - self-organization and conformational exchange - are of great interest in our group.
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