We will develop and apply theoretical methods for the study of structure and function of metalloproteins with high scientific, medicinal, and industrial interest. For example, will study the reaction mechanisms of nitrogenases, lytic polysaccharide monooxygenases, hydrogenases and particulate methane monooxygenases. We will also calibrate methods to calculate reduction potentials and acid constants in proteins. We will test and develop accurate multireference QM methods to use for metal cofactors. The project builds on the unique methods developed in our group, viz. methods to combine quantum mechanical (QM) and molecular mechanics (MM) calculations with experimental data, as well as method to calculate free energies at the QM/MM level. In particular, we will use calculations with very big QM systems (600–1000 atoms) and employ advanced wavefunction methods.
We will also develop and improve methods to predict the binding free energy of drug candidates to their receptor (a protein or a nucleic acid). This is one of the greatest challenges in drug development: If the binding affinity could be accurately predicted, the synthesis of most of the drug candidates could be avoided, which could save an enormous amount of money and time. We will improve free-energy perturbations by considering properties of water molecules in the binding site and by improving the potential-energy function using QM methods. In cooperation with experimental groups, we will study conformational entropies and the effect of water molecules. We will develop methods to interpret and improve neutron and X-ray structures and to obtain entropies from NMR and X-ray experiments.