Research Overview: From Conformational Dynamics to Mechanisms and Disease

RNA Viruses: The genetic structure of RNA viral populations (quasi-species) determine their intra-host evolution, rapid adaptation and hence their pathogenesis. Host immune pressure plays a unique role in RNA virus evolution. Viruses such as hepatitis C (HCV) evolve multiple mechanisms to disrupt immune signaling cascades with a net multilayered effect leading to immune escape and/or immune modulation. Such mechanisms are pivotal for viral persistence, treatment failure and ongoing liver injury probably even after apparent successful viral eradication. Our goal is to identify and characterize molecular principles that explain dynamic changes in viral quasi-species and adaptation on host factors to explore basic aspects of immune modulation and escape from immune and/or drug pressure in RNA virus infection.

Welsch et al., J Hepatol 2015; 2015 Apr;62(4):779-84.

Funding: German Research Foundation (DFG), Deutscher Akademischer Austauschdienst (DAAD) and Goethe University-Funds.

(I)  Adaptation at Protein-Lipid Interfaces: Folding, structure and function of membrane-bound proteins are influenced by their lipid environments with proteins binding lipids selectively to modulate their structure and respective function. Interference with protein–lipid interactions represents attractive opportunities for the development of novel therapies in various diseases. Using infectious cell culture and biophysics assays we characterize mechanistic details that enable perturbations at protein-lipid interfaces to initiate conformational changes.

 

Funding: Else Kröner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation - Pharma (TRIP)

 

(II)   Principles in Evolutionary Design of Proteins: Residue networks are powerful tools to analyze multiple sequence and protein structure data. Here we apply bioinformatics algorithms to understand statistical properties of viral proteins related to the dynamics of selection between specific conformational states on an RNA virus evolutionary time scale. Our aim is to understand the physical basis and underlying molecular principles that are known to be captured as an evolutionary fingerprint in the sequence information of a respective protein and are likely relate to changing conditions in fitness.

Welsch et al., AAC 2012;56(4):1907-15 Welsch et al., Gastroenterology 2012;142(3):654-63

Funding: German Research Foundation (DFG)  

Liver Immunology: Using our bioinformatics and structure biology tools we work in close collaboration with AG Lange on molecular structural aspects of the immune system of the liver in health and disease. A special emphasis is made on the resolution of liver inflammation.

Funding: Landes-Offensive zur Entwicklung Wissen­schaftlich-ökonomischer Exzellenz (LOEWE) - Research Center for Translational Medicine and Pharmacology TMP.

 

Staff:

PD Dr. med. Christoph Welsch, Group Leader (christoph.welsch@kgu.de)

Phone: +49 69 6301 4840

 

University Hospital Frankfurt               Max Planck Institute for Informatics
Goethe University                                Computational Biology & Applied Algorithmics
Department of Internal Medicine I       Campus E1 4
Theodor-Stern-Kai 7                            66123 Saarbrücken
60590 Frankfurt/Main
 

Dr. rer. nat. Claudia Stross, PostDoc (Claudia.Stross @gmx.de)

Dr. rer. nat. Katrin Bäumer, PostDoc (Haselow@med.uni-frankfurt.de)

Dr. med. Georg Dultz, PostDoc (Georg.Dultz@kgu.de)

Christian Grimm, PhD student (Grimm@em.uni-frankfurt.de)

Michael Konetschnik, MD student (Michael.Konetschnik@web.de)

 

Methods:

Bioinformatics, Biochemistry, Molecular Virology, Structure Biology

 

Cooperations:

Mario Albrecht, Bio MedTech-Graz, University of Technology, Austria

Iris Antes, Protein Modelling, Technical University Munich

Francisco S. Domingues, EURAC Research Bozen, Italy

Stanley M. Lemon, University of North Carolina at Chapel Hill (USA)

Thomas Lengauer, Max Planck Institute for Informatics, Saarbrücken

Tetsuro Shimakami, Gastroenterology Department, Kanazawa University, Japan

Robert Tampé, Institute of Biochemistry, Goethe University-Frankfurt

 

Funding:

Our research projects are supported by the Deutsche Forschungsgemeinschaft (DFG), the Else Kröner-Fresenius-Stiftung (EKFS), the Landes-Offensive zur Entwicklung Wissen­schaftlich-ökonomischer Exzellenz (LOEWE), Deutscher Akademische Austauschdienst (DAAD) and by the Goethe-University Frankfurt.<