Title:	Quantum chemical studies of biochemical reaction mechanisms
DNr:	NAISS 2025/22-221
Project Type:	NAISS Small Compute
Principal Investigator:	Margareta Blomberg <margareta.blomberg@su.se>
Affiliation:	Stockholms universitet
Duration:	2025-03-01 – 2026-03-01
Classification:	10407
Keywords:

Abstract

The general goal of my research is to elucidate enzyme mechanisms, in particular for redox active enzymes containing transition metals. For this purpose quantum chemical methods (mainly hybrid Density Functional Theory, DFT) are used to study biochemical model systems. My main project concerns mechanisms for enzymes that reduce molecular oxygen and/or nitric oxide. Therefore I study the reactions in heme-copper oxidases, such as cytochrome c oxidase (CcO), the terminal enzyme in the respiratory chain and cytochrome c dependent nitric oxide reductase (cNOR), involved in the nitrogen cycle. For the NO reduction there is still no consensus regarding which mechanism is actually followed. I have a close collaboration with the experimental groups working on these enzymes at Stockholm University (Peter Brzezinski and Pia Ädelroth), which has turned out to be very fruitful. Recently I have started to study mechanisms for another group of enzymes which also reduce both molecular oxygen and nitric oxide, the flavin dependent non-heme diiron proteins (FDPs). Initially I determined the mechanisms for both NO and O2 reduction in the FDP from Theromotoga maritima. A paper on the NO reduction was published in 2023 in the journal ACS Catalysis and a paper on the O2 reduction was published in 2024 in the Journal of Inorganic Biochemistry. During the last year I have extended the study to include both an FDP from another species, Desulfovibro gigas, and FDP-variants of Theromotoga maritima. The purpose is to try to explain differences in reduction activities between the different FDPs. A manuscript on the reduction of O2 and NO in FDPs has been submitted, in which the effects on the reaction energetics from variations in the second sphere ligands to the di-iron active site are discussed. I have recently started calculations on an FDP-model from still another species, Methanohermobacter marburgensis, to continue the investigation on the role of the second sphere residues. This FDP is of particular interest because it is missing a second sphere tyrosine that is conserved in all other FDPs, and from the available experimental information it seems to only reduce molecular oxygen and not nitric oxide. Another FDP that I am planning to study is the one from E. coli, which on the contrary seems to only reduce nitric oxide and not molecular oxygen.