Title:	Quantum chemical studies of biochemical reaction mechanisms
DNr:	NAISS 2024/22-147
Project Type:	NAISS Small Compute
Principal Investigator:	Margareta Blomberg <margareta.blomberg@su.se>
Affiliation:	Stockholms universitet
Duration:	2024-02-12 – 2025-03-01
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. One of my main projects concerns mechanisms for enzymes involved in cellular respiration. Therefore I study the reduction of molecular oxygen and proton pumping in cytochrome c oxidase (CcO), the terminal enzyme in the respiratory chain. Another enzyme belonging to the same family as CcO is nitric oxide reductase (cNOR), which reduces nitric oxide to nitrous oxide and water. 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. In particular, further studies on the NO reduction in cNOR will be performed in collaboration with Pia Ädelroth, with both calculations and experiments. Recently I have started to study mechanisms also for other enzymes forming nitrous oxide from nitric oxide, starting with the flavin dependent non-heme diiron proteins (FDPs). For the FDPs there is important experimental information available, but there is no consensus on the reaction mechanism. My calculations have given strong evidence for one type of mechanism, and the description of the reaction path agrees with the most important experimental information. A paper on this was published in 2023 in the journal ACS Catalysis. Similar to the heme-Cu oxidases, the FDPs can perform both NO and oxygen reduction, and I have during the last year studied also the mechanism for the oxygen reduction. A manuscript on oxygen reduction in FDPs has been submitted, in which a mechanism is suggested where a proton coupled reduction of the diferrous active site has to occur before the O-O bond can be cleaved. To study the mechanisms for both NO and oxygen reduction in different enzymes provides new insights, such as the role of an active site tyrosine in one particular of those enzymes. In the following I will also investigate the effects of mutations near the active site in the FDPs for which there is experimental information available.