Description of Research Group
Our main activity involves the use of computer modelling to solve complex questions in chemistry and biology with emphasis on enzyme and ligand design. Software development to facilitate investigations of macromolecular
complexes and to make more accurate computer models are also core activities.
Enzyme design has historically focused on activity and stability with little or no attention paid to the contributions from enthalpy and entropy. The enormous rate enhancement achieved by enzymes is often a result of a reduction of the activation enthalpy rather than the entropy. Computer simulations have not until very recently been able to capture these effects, mainly due to the lack of methods able to efficiently sample the configurational space. We have recently developed an approach that allows us to calculate activation enthalpies and entropies analogous to experimental Arrhenius plots, which we are currently using to uncover evolutionary principles behind enzymatic temperature adaptation. This information is then used to design enzyme variants with
Another aspect that is of interest to enzyme design is protein stability. This is normally more well understood, but difficult to predict prior to experimental testing. We are currently developing computational methods to enable
accurate prediction of protein stability and the effect of point mutations on the folding free energy.
Ligand or substrate binding is also important when it comes to our understanding of enzyme catalysis. Here, we
are developing methods able to predict not only the free energy of binding, but also its enthalpic and entropic
contributions using van’t Hoff plots.
Technology, expertise and equipment
Key expertise relevant to BioCat includes ligand/substrate docking, molecular dynamics simulations, free energy simulations of binding and catalysis.
Access to Schrödinger’s software for modelling of biological molecules including macromolecules on both local and national computing resources.
Our own software developed for EVB simulations and free energy simulations is also available.