Reaction mechanism of formate dehydrogenase studied by computational methods

Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry
Geng Dong, Ulf Ryde

Abstract

Formate dehydrogenases (FDHs) are metalloenzymes that catalyse the reversible conversion of formate to carbon dioxide. Since such a process may be used to combat the greenhouse effect, FDHs have been extensively studied by experimental and theoretical methods. However, the reaction mechanism is still not clear; instead five putative mechanisms have been suggested. In this work, the reaction mechanism of FDH was studied by computational methods. Combined quantum mechanical and molecular mechanic (QM/MM) optimisations were performed to obtain the geometries. To get more accurate energies and obtain a detailed account of the surroundings, big-QM calculations with a very large (1121 atoms) QM region were performed. Our results indicate that the formate substrate does not coordinate directly to Mo when it enters the oxidised active site of the FDH, but instead resides in the second coordination sphere. The sulfido ligand abstracts a hydride ion from the substrate, giving a Mo(IV)-SH state and a thiocarbonate ion attached to Cys196. The latter releases CO2 when the active site is oxidised back to the resting (MoVI) state. This mechanism is supported by recent experimental studies.

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Citations

Nov 22, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·Junhyeok SeoEunsuk Kim
Jul 7, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Henrique S FernandesNuno M F S A Cerqueira
Aug 18, 2020·Journal of Inorganic Biochemistry·Geng DongEn-Min Li
Jun 9, 2021·The Protein Journal·Aişe ÜnlüBarış Binay

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Methods Mentioned

BETA
electron paramagnetic resonance

Software Mentioned

PROPKA
dftd3
ComQum
SV
Turbomole
MPT
def2
thermo
TPSS
TZVP

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