Group Members

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Georg Kuenze

Current Post-Doctoral Fellow

BSc, MSc, PhD in Biochemistry University of Leipzig
georg.kuenze [ at ] vanderbilt.edu

Research Interests:

My   long-term   research   interest   is   the   study   of   structure-function   relationships   in   proteins   at   the molecular   level   using   a   multidisciplinary   approach   combining   experimentation   with   computational prediction. My postdoctoral research is devoted to the development and application of methods for the structure   determination   of   proteins   from   sparse   experimental   data.   In   the   Meiler   lab,   we   employ integrative modeling techniques, which consider multiple types of experimental data simultaneously, and are particularly crucial for the study of large and dynamic proteins, protein complexes, or membrane proteins, which are targets for half of therapeutics on the market. Our approach relies on reporter group techniques (e.g. NMR, EPR, and mass spectrometry) to obtain long-range distance information and capture the intricate structural dynamics in those proteins. This information is leveraged and interpreted by computational modeling with the Rosetta macromolecular software suite. Building on my previous doctoral training in NMR spectroscopy, I developed a new Rosetta framework for using paramagnetic NMR restraints in protein structure calculations. Paramagnetic NMR data can be obtained by tagging proteins   with   metal   ions   or   nitroxide   spin-labels,   and   provide   a   rich   amount   of   information   on   the position, orientation, and mobility of residues within the protein. In the future, I plan to expand Rosetta’s integrative   modeling   toolbox   by   additional   reporter   group   techniques   (including   data   from   FRET, crosslinking, and NMR), and exploit the potential of new machine learning algorithms for more accurate and faster calculation of structural restraints.

I   am   equally   interested   in   method   development   and   application.   In   collaboration   with   scientists   at Vanderbilt   and   from   research   groups   worldwide,   I   create   integrative   models   of   pharmacologically interesting proteins (e.g. Bradykinin G-protein coupled receptors, the bacterial-sensing histidine kinase NsaS,   and   the   nuclear   receptor   LHR-1)   as   basis   to   answer   mechanistic   questions   about   protein function, and as starting point for structure-guided drug design efforts. My long-term interest is dedicated towards the structure and function of ion channels which play essential roles in numerous physiological processes throughout the body. Together with the labs of Charles Sanders at Vanderbilt University and Alfred George at Northwestern University, I am currently studying the voltage-gated potassium channel KCNQ1. Mutations in KCNQ1 are associated with various cardiac pathologies, e.g. long QT syndrome.

The impressive increase of genome sequencing data in the last years has revealed the existence of hundreds of nonsynonymous single-nucleotide variants in KCNQ1 and other ion channels, however, the molecular mechanisms and functional implications for many of them remain unknown. At the same time, cryo-EM   technology   has   provided   numerous   new   structures   of   ion   channels   raising   exciting   new hypotheses about their function and providing a solid structural biology framework for computational modeling. Using Rosetta and molecular dynamics simulations, informed by data from biochemical and electrophysiology experiments, I aim to answer questions related to the molecular mechanisms of ion channel gating, transition from closed to open channel states, beta-subunit regulation, and the role of mutations in KCNQ1.