Density functional theory studies on the conversion of hydroxyheme to iron-verdoheme in the presence of dioxygen

Gheidi, Mahin; Safari, Nasser; Zahedi, Mansour

doi:10.1039/c6dt04250c

Cited by 9 publications

(14 citation statements)

References 59 publications

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“…As is shown in Figure 3 , this involves five states and four transition states. It starts from the Fe III -OXF–

complex in the doublet state ( 1 ), which has one unpaired electron on each of the three moieties, in analogy with previous studies (Alavi et al, 2017 ; Gheidi et al, 2017 ). In the first step of the reaction, the terminal oxygen atom in O 2 (O2) reacts with the C4B atom of OXF, forming a bridging intermediate ( 2 ).…”

Section: Resultssupporting

confidence: 56%

On the Difference Between Additive and Subtractive QM/MM Calculations

Cao

Ryde

2018

Front. Chem.

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The combined quantum mechanical (QM) and molecular mechanical (MM) approach (QM/MM) is a popular method to study reactions in biochemical macromolecules. Even if the general procedure of using QM for a small, but interesting part of the system and MM for the rest is common to all approaches, the details of the implementations vary extensively, especially the treatment of the interface between the two systems. For example, QM/MM can use either additive or subtractive schemes, of which the former is often said to be preferable, although the two schemes are often mixed up with mechanical and electrostatic embedding. In this article, we clarify the similarities and differences of the two approaches. We show that inherently, the two approaches should be identical and in practice require the same sets of parameters. However, the subtractive scheme provides an opportunity to correct errors introduced by the truncation of the QM system, i.e., the link atoms, but such corrections require additional MM parameters for the QM system. We describe and test three types of link-atom correction, viz. for van der Waals, electrostatic, and bonded interactions. The calculations show that electrostatic and bonded link-atom corrections often give rise to problems in the geometries and energies. The van der Waals link-atom corrections are quite small and give results similar to a pure additive QM/MM scheme. Therefore, both approaches can be recommended.

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“…As is shown in Figure 3 , this involves five states and four transition states. It starts from the Fe III -OXF–

Section: Resultssupporting

confidence: 56%

On the Difference Between Additive and Subtractive QM/MM Calculations

Cao

Ryde

2018

Front. Chem.

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“…This reaction was considered in our previous study. 13,14 The ring opening mechanism from oxophlorin to biliverdin has been investigated for three Fe ligands CO, O2 and H2O by QM/MM calculations at the TPSS-D3/def2-SV(P) level and at the B3LYP/6-311+G** level in QM-cluster calculations. The QM/MM results were then improved by big-QM calculations using a very large QM region of almost 1000 atoms and the energies were extrapolated to theB3LYP-D3 method and the def2-QZVP basis set.…”

Section: Discussionmentioning

confidence: 99%

“…In this paper, we propose a new heme cleavage mechanism, suggesting that whereas a fivecoordinated hydroxyheme may form verdoheme when it reacts with O2 13,14 , if the Fe ion binds the released CO molecule or water as the sixth ligand, the reaction with O2 instead leads to ring opening and biliverdin production. Thus, both biliverdin and verdoheme production can occur simultaneously, which is corroborated by experimental evidence.…”

Section: Introductionmentioning

confidence: 99%

“…Since iron has a high positive charge, the former possibility is 35 kcal/mol more favorable than the second one. 13,14 Previous QM and QM/MM studies has shown that Fe-coordinated O2 can react with the heme ring, resulting in the formation of verdoheme. 13,14 However, if the sixth position of the iron ion is occupied with another molecule (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…13,14 Previous QM and QM/MM studies has shown that Fe-coordinated O2 can react with the heme ring, resulting in the formation of verdoheme. 13,14 However, if the sixth position of the iron ion is occupied with another molecule (e.g. CO, H2O or O2; H2O and O2 are available in the enzyme environment and CO is formed during the conversion of the oxophlorin to verdoheme), O2 may react differently, yielding instead biliverdin.…”

Section: Introductionmentioning

confidence: 99%

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A novel mechanism of heme degradation to biliverdin studied by QM/MM and QM calculations

et al. 2018

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Heme degradation by heme oxygenase enzymes is important for maintaining iron homeostasis and prevention of oxidative stress. Previous studies have reported that heme degradation proceeds through three consecutive steps of O2 activation: the regiospecific self-hydroxylation of heme, the conversion of hydroxyheme to verdoheme and CO, and the cleavage of the verdoheme macrocycle to release biliverdin and free ferrous iron. Our results indicate that in the second step of heme degradation, not only verdoheme is generated but ring opening and biliverdin production also occur. We have performed QM-cluster and QM/MM calculations, which show that calculations with H2O as the axial ligand of Fe give the lowest barrier. In the QM-cluster calculation, the reaction is exothermic by -85 kcal mol-1 and the rate-limiting barrier is 5 kcal mol-1, whereas the corresponding QM/MM calculations give a slightly lower barrier of 3 kcal mol-1, owing to strong hydrogen bonds and the protein environment.

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