Computational Understanding of Biocatalytic Evolution to Extreme Environments

The project will focus on evolutionary principles behind adaptation to extreme environments with emphasis on how temperature affects the stability and activity of enzymes and ribosomes. This will be achieved by connecting the underlying microscopic energetics of the macromolecular structures with macroscopic observables using computational approaches pioneered by Brandsdal and Åqvist. Predictions made with computations will then be tested and verified by experiments. The contribution to the free energy from enthalpy and entropy remains highly challenging to calculate, particularly when dealing with large complex biological macromolecules involved in catalysis and binding events. The core activities of CUBE3 are centered on suggested hypothesis of how evolution changes the enthalpy-entropy balance to allow enzymes to function near the freezing point of water, as discussed in our recent publication in Nature Reviews of Chemistry. The interest in enzymes from extremophiles is also immense from an industrial and biotechnological point of view, due to their potential use as biocatalysts either in their natural form or engineered variants


The primary objective of CUBE3 is to understand the principles responsible for the universal enthalpy-entropy changes involved in temperature adaptation of biocatalysts. Secondary objectives are to 1) calculate the thermodynamic activation parameters of enzymes and ribosomes, 2) develop computational tools to disentangle activity and stability mutations, 3) develop methods for understanding of the temperature dependence of substrate binding, 4) create, develop and validate experimental data and computational models on catalytic activity and stability, and 5) provide new software to the international community at no cost. This objective will be reached through five work packages:

  1. Temperature dependence of catalytic rates of different thermally adapted enzyme orthologues and ribosomes (read more).
  2. Develop computational tools and protocols to pinpoint residual hot spots important to thermal stability (read more).
  3. Develop computational tools and protocols to enable calculation of free energies, enthalpies and entropies of substrate binding (read more).
  4. Experimental characterization and design (read more).
  5. Visualization and analysis of large data sets (read more).


The project is carried out at the Tromsø node of the Hylleraas Cente for Quantum Molecular Sciences, a new Centre of Excellence establishe for a 10-year period 2017-2027. The Hylleraas Centre gathers world-leading expertise in the domains of electronic-structure theory, multiscale modelling, computational spectroscopy, and the use of computation to understand and control complex chemical and biological systems. Through an extensive incoming sabbatical programme, a generous visitors programme, focus bienniums, international workshops, conferences, outreach activities and seminar series, the Hylleraas Centre will create an internationally visible and attractive centre for the computational modelling and understanding of new chemistry at the frontiers of a wide range of scientific disciplines.