Computational applications and method development for the study of enzymes

We will develop, calibrate, compare and apply advanced computational methods to study the structure and function of enzymes with high scientific, medicinal and industrial interest, e.g. nitrogenase, hydrogenase, triosephosphate isomerase, lytic polysaccharide monooxygenase, methane monooxygenase, sulfite reductase, CO dehydrogenase and formate dehydrogenase.

We will also calculate reduction potentials and acidity constants of metalloproteins.

The project builds on a set of unique methods developed in our group, viz. approaches to integrate quantum mechanical (QM) and molecular mechanics (MM) calculations, often in combination with experimental methods (X-ray or neutron structures), to estimate free energies at the QM/MM level, to use very large QM systems, tailored force fields or polarisable-embedding QM/MM calculations, and to calibrate the calculations using high-level QM methods.

We will also compare with approaches employed in other groups, e.g. QM-cluster, empirical valence bond and metadynamics calculations.

The project will provide enhanced knowledge of the function of many key enzymes and it will show what computational methods to trust and use for mechanistic studies of enzymes. I will coordinate the project, involving 1 new PhD student and 1.5 old students.

Moreover, it involves tight cooperations with 4 groups outside Sweden, performing mainly application of our methods on specific enzymes. The project will run over four years.