Computational analysis and design of enzyme adaptation to extreme environments

This project will launch a major combined computational and experimental effort aimed at explaining the structural and energetic principles of enzyme evolution and adaptation to the external environment.

Particularly, the principles of adaptation of natural enzymes from different species to extreme temperatures and pressures remains a major unsolved problem.

We have developed a unique computational approach during the last decade for attacking these problems by computer simulations.

This has led to the discovery that temperature adaptation is largely associated with mutations on the enzyme surface, which modulate its rigidity.

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.

The key parameters both in temperature and pressure adaptation are the catalytic rates, substrate binding affinities and protein stability.

It is thus essential to disentangle the effects of adaptive mutations on these different quantities and also to distinguish random mutations from significant ones.

In this project, we will now explore, both with computations and experiments, a number of different classes of enzymes from differently adapted species in order to understand how evolution has operated.

An overall goal here is to be able to rationally design and redesign the physico-chemical properties of enzymes, which our recent results show is possible.