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Towards rational improvement of protein stability: A combined computational and NMR spectroscopic approach.

Carlsbergfondets postdoc-stipendier i Danmark

What

Proteins are complex biomolecules that are the workhorses for all biological processes. Proteins are also widely used in both technical and medical applications, such as enzymes in laundry detergents, or as protein pharmaceuticals. Most proteins need to fold into a well-defined three-dimensional structure to function. The stability of a protein determines how well the protein can perform this folding process, and having a detailed understanding of protein stability is thus key to our ability to optimize proteins, and understand how they can lose function in disease. The goal of this project is thus to improve our ability to predict the effect of mutations on protein stability.

Why

The ability to predict how mutations change the stability of a protein can be used in medical genetics to better understand the mechanism of a range of genetic disorders. In biotechnology, mutations that increase the stability of a protein without affecting its function may be used to increase the resistance of enzymes, or protein pharmaceuticals to environmental factors (e.g. to heat). In this way, stabilizing mutations can improve the efficiency of medical products and increase their shelf life. The effect of mutations on protein stability was investigated before. However, known experimental methodology and theoretical state-of-the-art prediction methods fail to predict and describe the effect of many mutations. Thus, there is a possibility for further improvements in this field.

How

My strategy is to combine experimental measurements of how atoms move and vibrate in the protein with advanced computer simulations. By analyzing several mutants of a protein in this way, I will be able to elucidate how the structure, the atomic motions and the stability depend on each other. This approach adds an extra layer to our understanding of protein stability, which will be built into models that more accurately can predict the effect of any mutation on the stability of a protein.

SSR

The project has important applications both within the area of personalized medicine, and in our ability to use proteins in technical or medical applications. In the area of medicine, our research will improve our ability to use DNA sequencing methods to diagnose patients, and to provide mechanistic models for diseases that might suggest avenues for new treatments. In biotechnology, enzymes are widely used as environmentally friendly substitutes for harsh chemicals, and by making enzymes more stable we can use them for new tasks. Also, by making protein pharmaceuticals (such as insulin, hormones, antibodies) more stable, we may increase their shelf life and make it possible to use such drugs also in less developed countries where controlled storage is a key concern.