Åqvist lab

Our research is focused on analysis and predictions of function and interactions of biological macromolecules using various computational and bioinformatical methods. Through the use of modern computational methods it is possible to perform large-scale simulations of biological macromolecules such as proteins and nucleic acids. We are especially interested in the energetics of ligand binding and biological catalysis. Current projects include studies enzyme evolution and adaptation to extreme environments as well as computational enzyme design.

Popular science presentation

Our research deals with design of new enzymes based on our understanding of how evolution has managed to create enzymes that can work under extreme conditions. This pertains, for example, to enzymes from different microorganisms that can function despite strong cold or heat, under very acidic conditions, under extremely high pressure or salt concentration. Also cold-adapted fishes that live near the freezing point of liquid water have enzymes that can catalyze chemical reactions despite the cold conditions. The amino acid sequences of cold- and warm-adapted orthologous enzymes are often very similar and there are a limited number of mutations that cause the adaptation to environmental conditions. It turns out that mutations that have to do with temperature optimization mainly are located on the surface of the enzyme. This knowledge has now led to our ability to design the enzyme temperature dependence through a combination of computation and biochemical experiments, which is of major biotechnological interest.

Research projects

Our projects are focused on computational design of new enzymes based on our understanding of existing ones from extremophilic species. We have been working with enzymes from psychrophilic (cold-adapted), mesophilic and thermophilic species and analyzed the structural and energetic origins of their catalytic temperature dependence, both by computer simulations and experiments. A major problem has been to explain how cold-adapted enzymes are able to work at low temperatures, where mesophilic and thermophilic enzymes have basically lost most of their activity. This involves calculations and experimental measurements of their catalytic rates, temperature optima and melting temperatures and we have now reached a point we are able to design these properties based on computations. It has led to our discovery that temperature adaptation is largely associated with mutations on the enzyme surface, which primarily modulate its flexibility. We could thus prove a direct connection between this phenomenon and the thermodynamic activation parameters of the catalyzed reaction, which in turn determine the temperature dependence of the rate. We have developed a unique computational approach during the last decade for attacking these problems by computer simulations and are now combining this with deep learning methods to design the temperature dependence of several types of enzyme reactions and validate the computational results by biochemical experiments. We have already succeeded with this type of computational design in a few cases. This also has many biotechnological applications and there is currently a huge interest in different types of extremophilic enzymes.

Q - our Molecular dynamics program

Q is a molecular dynamics package designed for free energy calculations in biomolecular systems.

The website for the package is found at:

https://github.com/qusers

And the full code under git versioning can be found at github under a GPL Version 2 License at:

https://github.com/qusers/Q6

A set of tutorials for starting simulations is also versioned at github and found here:

https://github.com/qusers/qtutorials

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