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Dr. Knut Teigen was born in Bergen, Norway, 20th of June 1974 and started a bachelors in Biochemistry at the University of Bergen in 1993. After obtaining his bachelor degree in 1998 he started working on his master’s thesis, partly in collaboration with Irwin Kuntz at The Molecular Design Institute in San Francisco, California. He defended his master’s thesis in 2000. He then started working on his PhD within the same field. The thesis was performed in collaboration with Angela Gronenborn at the National Institutes of Health in Bethesda where he also spent 6 months applying NMR to study protein ligand interactions. His thesis was defended in 2004 and He then started working as a postdoctoral fellow at the Department of Biomedicine in Bergen.
During his master’s and PhD thesis work, he applied mainly biophysical techniques (NMR, CD spectroscopy, differential scanning and isothermal titration calorimetry) in combination with mutagenesis, protein expression, protein purification and enzyme activity assays. As a postdoctoral fellow he moved more into the field of structural and computational biology. He initiated collaboration with David Case at the Scripps Research Institute in La Jolla, California in 2005 and worked in his group for about half a year applying and developing methods to study protein ligand interactions that complement experimental techniques used in Bergen.
As of 1st of April 2008 he was appointed Associate Professor of the Medical Faculty, University of Bergen where he now is at the very beginning of starting up his own group. So far the group consists of himself and two master students in Pharmacy that study how cationic amphiphilic drugs interact with biological membranes, using both experimental (Langmuir monolayer techniques and Atomic Force Microscopy) and computational methods (Docking and Molecular Dynamics). He hopes to be able to offer at least one PhD position shortly that will be in collaboration with David Case, developing force field parameters for lipid simulations and applying them to study drug membrane interactions.
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Combining experimental and computational methods to study protein ligand complexes
Knut Teigen, Department of Biomedicine, University of Bergen, Norway
Computational methods have been applied in our group in combination with experimental techniques to get a deeper understanding of the affinity and selectivity determinants concerning protein ligand complexes. Of particular interest has been the family of enzymes carrying out hydroxylation of aromatic amino acids referred to as the aromatic amino acid hydroxylases (AAH). Mutations and dysfunction of these enzymes are associated to phenylketonuria (phenylalanine hydroxylase), Parkinson’s disease and DOPA-responsive dystonia (tyrosine hydroxylase), autoimmunity and affective disorders (tryptophan hydroxylase).
The aromatic amino acid hydroxylases (AAHs) have been the subject of extensive research and experimental investigation for more than half a century. The elucidation of the 3D structure of the AAHs opened up a new era in the study of these enzymes. The ability to access and study the information contained in the structures made it possible to understand the vast amount of experimental data acquired throughout the preceding decades from a new perspective. The structures of the ligand-bound forms of the enzymes opened the opportunity for rational discussions of structure-function-energetics relationships.
By combining computational and experimental methods in the study of these enzymes we get a more comprehensive understanding of their function than either approach could give us alone. NMR provides us with interatomic distance restraints for the ligands free in solution and when bound to the different enzymes. These restraints are used in determining the conformation of the ligands as well as constraints in docking the ligands to the active site of the enzymes. Microcalorimetry gives us the thermodynamic properties of ligand binding and computer simulations provide us with a tool to understand the experimentally observed quantities. Based on these investigations we speculate that the differences in how the AAHs interact with cofactor may be exploited in the development of cofactor analogues designed for specific pharmacological regulation of each hydroxylase.
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