A low-order scaling incremental correlation method for the calculation of electronic excitation energies
Final Report Abstract
The project has explored the use of low-cost computational approaches to the simulation of electronic spectra in biomolecules. Approximations to the quantum mechanical treatment of electronic excitations as well the classical electrostatic embedding used for the description of the condensed phase have been studied. We have successfully applied the latter methods to the study of ThDP-dependent enzymes, uncovering a strong dependence of activation processes in the acid-base chemistry of the cofactor and surrounding residues. Application studies in the human transketolase system have revealed a new fundamental communication mechanism in enzymes. Some proteins hold internal hydrogen bond networks which can function as proton shuttles between active sites. The protons react to variations in the electrostatic potential of each pocket, moving back and forth, potentially synchronizing reactions and/or activating cofactors. This Newton cradle type of movement has been simulated and confirmed through molecular dynamics simulations of the proton wire, one-dimensional quantum mechanical treatment of protons and quantum mechanical/molecular mechanical simulations of the cofactor and interacting residues. These findings open the door to the development of new drugs, new scaffolds for bioinspired molecular switches and steered design of protein mutants with improved/reduced allostericity. The project has also opened the perspective of new high-throughput quantum mechanical treatments of UV-Vis absorption spectra through the use of quantum mechanics/molecular mechanics modeling and perturbation theory. The latter has been successfully applied to the study of thiamin enzymes and is now being extended to red fluorescent proteins of biotechnological interest.
Publications
- (2019) Low-barrier hydrogen bonds in enzyme cooperativity. Nature 573 (7775) 609–613
Dai, Shaobo; Funk, Lisa-Marie; Pappenheim, Fabian Rabe von; Sautner, Viktor; Paulikat, Mirko; Schröder, Benjamin; Uranga, Jon; Mata, Ricardo A.; Tittmann, Kai
(See online at https://doi.org/10.1038/s41586-019-1581-9) - Theoretical studies of the electronic absorption spectra of thiamin diphosphate in pyruvate decarboxylase, Biochemistry 56, 1854- 1864 (2017)
M. Paulikat, C. Wechsler, K. Tittmann and R. A. Mata
(See online at https://doi.org/10.1021/acs.biochem.6b00984) - Computational studies of ThDP-dependent enzymes, PhD thesis, University of Göttingen (2018)
M. Paulikat
