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.