Jens Meiler

Computational Structural Biochemistry

Research in my laboratory seeks to fuse computational and experimental efforts to investigate proteins, the fundamental molecules of biology. We develop computational methods with three major ambitions in mind: 1) to deepen our understanding of the protein folding process, 2) refine and accelerate protein structure elucidation approaches, and 3) understand existing or design novel protein ligand interactions. Crucial for our success is the experimental validation of our computational approaches. Current research projects include:

Design of symmetric TIM-barrel proteins. TIM barrel are among the most frequent folds in nature – in fact most of the protein structures solved in the protein databank are TIM barrel proteins. Their symmetry in structure raises questions about their evolutionary origin as well as their folding pathway and makes them ideal starting points for applications in protein design or nanotechnology. We shed light on these questions by designing TIM barrel proteins symmetric in structure and sequence.

Protein structure elucidation from low resolution/sparse experimental data. With the completion of the Human Genome Project scientists have access to sequence information of a vast number of proteins sequences. For many of these proteins – in particular membrane proteins and/or huge complexes of dozens individual domains – tertiary structure elucidation becomes challenging: Datasets obtained from X-Ray crystallography or NMR spectroscopy are frequently of lesser quality and/or sparse compared to soluble proteins. Other methods like cryo-EM, EPR and FRET spectroscopy provide a new source for structural data. These sparse and novel experimental datasets place an increasing demand on computational methods for translation into structural information. We develop computer algorithms tailored for determining the structure from low resolution/sparse experimental data and apply them in collaboration with numerous experimental groups.

Redesign proteins into novel antibiotics. Vancomycin is the archetype among naturally occurring compounds known as glycopeptide antibiotics. Siderocalin, a member of the lipocalin family of binding proteins, is an antibacterial protein by sequestering iron as ferric siderophore complexes. We follow the strategy to redesign existing proteins computationally to act analogous to vancomoycin or siderocalin. In this process we address known resistances and attempt to broaden to applicability of these antibiotics.

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