| 1. |
- Dong, Geng, et al.
(författare)
-
Effect of the protein ligand in DMSO reductase studied by computational methods
- 2017
-
Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134. ; 171, s. 45-51
-
Tidskriftsartikel (refereegranskat)abstract
- The DMSO reductase family is the largest and most diverse family of mononuclear molybdenum oxygen-atom-transfer proteins. Their active sites contain a Mo ion coordinated to two molybdopterin ligands, one oxo group in the oxidised state, and one additional, often protein-derived ligand. We have used density-functional theory to evaluate how the fourth ligand (serine, cysteine, selenocysteine, OH−, O2–, SH−, or S2–) affects the geometries, reaction mechanism, reaction energies, and reduction potentials of intermediates in the DMSO reductase reaction. Our results show that there are only small changes in the geometries of the reactant and product states, except from the elongation of the Mo[sbnd]X bond as the ionic radius of X[dbnd]O, S, Se increases. The five ligands with a single negative charge gave an identical two-step reaction mechanism, in which DMSO first binds to the reduced active site, after which the S[sbnd]O bond is cleaved, concomitantly with the transfer of two electrons from Mo in a rate-determining second transition state. The five models gave similar activation energies of 69–85 kJ/mol, with SH− giving the lowest barrier. In contrast, the O2– and S2– ligands gave much higher activation energies (212 and 168 kJ/mol) and differing mechanisms (a more symmetric intermediate for O2– and a one-step reaction without any intermediate for S2–). The high activation energies are caused by a less exothermic reaction energy, 13–25 kJ/mol, and by a more stable reactant state owing to the strong Mo[sbnd]O2– or Mo[sbnd]S2– bonds.
|
|
| 2. |
- Dong, Geng, et al.
(författare)
-
Exploration of H2 binding to the [NiFe]-hydrogenase active site with multiconfigurational density functional theory
- 2018
-
Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 20:2, s. 794-801
-
Tidskriftsartikel (refereegranskat)abstract
- The combination of density functional theory (DFT) with a multiconfigurational wave function is an efficient way to include dynamical correlation in calculations with multiconfiguration self-consistent field wave functions. These methods can potentially be employed to elucidate reaction mechanisms in bio-inorganic chemistry, where many other methods become either too computationally expensive or too inaccurate. In this paper, a complete active space (CAS) short-range DFT (CAS-srDFT) hybrid was employed to investigate a bio-inorganic system, namely H2 binding to the active site of [NiFe] hydrogenase. This system was previously investigated with coupled-cluster (CC) and multiconfigurational methods in the form of cumulant-approximated second-order perturbation theory, based on the density matrix renormalization group (DMRG). We find that it is more favorable for H2 to bind to Ni than to Fe, in agreement with previous CC and DMRG calculations. The accuracy of CAS-srDFT is comparable to both CC and DMRG, despite much smaller active spaces were employed than in the corresponding DMRG calculations. This enhanced efficiency at the smaller active spaces shows that CAS-srDFT can become a useful method for bio-inorganic chemistry.
|
|
| 3. |
- Dong, Geng, et al.
(författare)
-
H2 binding to the active site of [NiFe] hydrogenase studied by multiconfigurational and coupled-cluster methods
- 2017
-
Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 19:16, s. 10590-10601
-
Tidskriftsartikel (refereegranskat)abstract
- [NiFe] hydrogenases catalyse the reversible conversion of molecular hydrogen to protons and electrons. This seemingly simple reaction has attracted much attention because of the prospective use of H2 as a clean fuel. In this paper, we have studied how H2 binds to the active site of this enzyme. Combined quantum mechanical and molecular mechanics (QM/MM) optimisation was performed to obtain the geometries, using both the TPSS and B3LYP density-functional theory (DFT) methods and considering both the singlet and triplet states of the Ni(ii) ion. To get more accurate energies and obtain a detailed account of the surroundings, we performed calculations with 819 atoms in the QM region. Moreover, coupled-cluster calculations with singles, doubles, and perturbatively treated triples (CCSD(T)) and cumulant-approximated second-order perturbation theory based on the density-matrix renormalisation group (DMRG-CASPT2) were carried out using three models to decide which DFT methods give the most accurate structures and energies. Our calculations show that H2 binding to Ni in the singlet state is the most favourable by at least 47 kJ mol-1. In addition, the TPSS functional gives more accurate energies than B3LYP for this system.
|
|
| 4. |
- Dong, Geng, et al.
(författare)
-
Insight into the reaction mechanism of lipoyl synthase : a QM/MM study
- 2018
-
Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 23:2, s. 221-229
-
Tidskriftsartikel (refereegranskat)abstract
- Lipoyl synthase (LipA) catalyses the final step of the biosynthesis of the lipoyl cofactor by insertion of two sulfur atoms at the C6 and C8 atoms of the protein-bound octanoyl substrate. In this reaction, two [4Fe4S] clusters and two molecules of S-adenosyl-l-methionine are used. One of the two FeS clusters is responsible for the generation of a powerful oxidant, the 5′-deoxyadenosyl radical (5′-dA•). The other (the auxiliary cluster) is the source of both sulfur atoms that are inserted into the substrate. In this paper, the spin state of the FeS clusters and the reaction mechanism is investigated by the combined quantum mechanical and molecular mechanics approach. The calculations show that the ground state of the two FeS clusters, both in the [4Fe4S]2+ oxidation state, is a singlet state with antiferromagnetically coupled high-spin Fe ions and that there is quite a large variation of the energies of the various broken-symmetry states, up to 40 kJ/mol. For the two S-insertion reactions, the highest energy barrier is found for the hydrogen-atom abstraction from the octanoyl substrate by 5′-dA•. The formation of 5′-dA• is very facile for LipA, with an energy barrier of 6 kJ/mol for the first S-insertion reaction and without any barrier for the second S-insertion reaction. In addition, the first S ion attack on the C6 radical of octanoyl was found to take place directly by the transfer of the H6 from the substrate to 5′-dA•, whereas for the second S-insertion reaction, a C8 radical intermediate was formed with a rate-limiting barrier of 71 kJ/mol.
|
|
| 5. |
- Dong, Geng, et al.
(författare)
-
O2 activation in salicylate 1,2-dioxygenase : A QM/MM study reveals the role of His162
- 2016
-
Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 55:22, s. 11727-11735
-
Tidskriftsartikel (refereegranskat)abstract
- Nonheme iron enzymes play an important role in the aerobic degradation of aromatic ring systems. Most enzymes can only cleave substrates with electron-rich substituents, e.g., with two hydroxyl groups. However, salicylate 1,2-dioxygenase (SDO) can cleave rings with only a single hydroxyl group. We investigated the oxygen-activation mechanism of the ring fission of salicylate by SDO by computational methods using combined quantum mechanical and molecular mechanical (QM/MM) geometry optimizations, large QM calculations with 493 atoms, and QM/MM free-energy perturbations. Our results demonstrate that the reactive Fe-O2 species is best described as a Fe(III)-O2•- state, which is triplet O2 binding to quintet Fe(II), leading to a one-electron transfer from Fe(II) to O2. Subsequently, the O2•- group of this species attacks the aromatic ring of substrate to form an alkylperoxo intermediate. Mutation studies suggested that His162 is essential for catalysis. Our calculations indicate that His162 plays a role as an acid-base catalyst, providing a proton to the substrate.
|
|
| 6. |
- Dong, Geng, et al.
(författare)
-
Protonation states of intermediates in the reaction mechanism of [NiFe] hydrogenase studied by computational methods.
- 2016
-
Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 1432-1327 .- 0949-8257. ; 21:3, s. 383-394
-
Tidskriftsartikel (refereegranskat)abstract
- The [NiFe] hydrogenases catalyse the reversible conversion of H2 to protons and electrons. The active site consists of a Fe ion with one carbon monoxide, two cyanide, and two cysteine (Cys) ligands. The latter two bridge to a Ni ion, which has two additional terminal Cys ligands. It has been suggested that one of the Cys residues is protonated during the reaction mechanism. We have used combined quantum mechanical and molecular mechanics (QM/MM) geometry optimisations, large QM calculations with 817 atoms, and QM/MM free energy simulations, using the TPSS and B3LYP methods with basis sets extrapolated to the quadruple zeta level to determine which of the four Cys residues is more favourable to protonate for four putative states in the reaction mechanism, Ni-SIa, Ni-R, Ni-C, and Ni-L. The calculations show that for all states, the terminal Cys-546 residue is most easily protonated by 14-51 kJ/mol, owing to a more favourable hydrogen-bond pattern around this residue in the protein.
|
|
| 7. |
- Dong, Geng, et al.
(författare)
-
Reaction mechanism of formate dehydrogenase studied by computational methods
- 2018
-
Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 23:8, s. 1243-1254
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 8. |
- Dong, Geng, et al.
(författare)
-
Reaction Mechanism of [NiFe] Hydrogenase Studied by Computational Methods
- 2018
-
Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 57:24, s. 15289-15298
-
Tidskriftsartikel (refereegranskat)abstract
- [NiFe] hydrogenases catalyze the reversible conversion of molecular hydrogen to protons and electrons. This seemingly simple reaction has attracted much attention because of the prospective use of H2 as a clean fuel. In this paper, we have studied the full reaction mechanism of this enzyme with various computational methods. Geometries were obtained with combined quantum mechanical and molecular mechanics (QM/MM) calculations. To get more accurate energies and obtain a detailed account of the surroundings, we performed big-QM calculations with 819 atoms in the QM region. Moreover, QM/MM thermodynamic cycle perturbation calculations were performed to obtain free energies. Finally, density matrix renormalisation group complete active space self-consistent field calculations were carried out to study the electronic structures of the various states in the reaction mechanism. Our calculations indicate that the Ni-L state is not involved in the reaction mechanism. Instead, the Ni-C state is reduced by one electron and then the bridging hydride ion is transferred to the sulfur atom of Cys546 as a proton and the two electrons transfer to the Ni ion. This step turned out to be rate-determining with an energy barrier of 58 kJ/mol, which is consistent with the experimental rate of 750 ± 90 s-1 (corresponding to ∼52 kJ/mol). The cleavage of the H-H bond is facile with an energy barrier of 33 kJ/mol, according to our calculations. We also find that the reaction energies are sensitive to the size of the QM system, the basis set, and the density functional theory method, in agreement with previous studies.
|
|
| 9. |
- Jafari, Sonia, et al.
(författare)
-
Quantum Mechanics/Molecular Mechanics Study of the Reaction Mechanism of Glyoxalase I
- 2020
-
Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 1520-510X .- 0020-1669. ; 59, s. 2594-2603
-
Tidskriftsartikel (refereegranskat)abstract
- Glyoxalase I (GlxI) is a member of the glyoxalasesystem, which is important in cell detoxification and convertshemithioacetals of methylglyoxal (a cytotoxic byproduct of sugarmetabolism that may react with DNA or proteins and introducenucleic acid strand breaks, elevated mutation frequencies, andstructural or functional changes of the proteins) and glutathioneinto D-lactate. GlxI accepts both the S and R enantiomers ofhemithioacetal, but converts them to only the S-D enantiomer oflactoylglutathione. Interestingly, the enzyme shows this unusualspecificity with a rather symmetric active site (a Zn ioncoordinated to two glutamate residues; Glu-99 and Glu-172),making the investigation of its reaction mechanism challenging.Herein, we have performed a series of combined quantummechanics and molecular mechanics calculations to study the reaction mechanism of GlxI. The substrate can bind to the enzyme in two different modes, depending on the direction of its alcoholic proton (H2; toward Glu-99 or Glu-172). Our results show that the S substrate can react only if H2 is directed toward Glu-99 and the R substrate only if H2 is directed toward Glu-172. In both cases, the reactions lead to the experimentally observed S-D enantiomer of the product. In addition, the results do not show any low- energy paths to the wrong enantiomer of the product from neither the S nor the R substrate. Previous studies have presented several opposing mechanisms for the conversion of R and S enantiomers of the substrate to the correct enantiomer of the product. Our results confirm one of them for the S substrate, but propose a new one for the R substrate.
|
|
| 10. |
- Larsson, Ernst D., et al.
(författare)
-
Is density functional theory accurate for lytic polysaccharide monooxygenase enzymes
- 2020
-
Ingår i: Dalton Transactions. - : Royal Society of Chemistry (RSC). - 1477-9226 .- 1477-9234. ; 49:5, s. 1501-1512
-
Tidskriftsartikel (refereegranskat)abstract
- The lytic polysaccharide monooxygenase (LPMO) enzymes boost polysaccharide depolymerization through oxidative chemistry, which has fueled the hope for more energy-efficient production of biofuel. We have recently proposed a mechanism for the oxidation of the polysaccharide substrate (E. D. Hedegård and U. Ryde, Chem. Sci., 2018, 9, 3866-3880). In this mechanism, intermediates with superoxide, oxyl, as well as hydroxyl (i.e. [CuO2]+, [CuO]+ and [CuOH]2+) cores were involved. These complexes can have both singlet and triplet spin states, and both spin-states may be important for how LPMOs function during catalytic turnover. Previous calculations on LPMOs have exclusively been based on density functional theory (DFT). However, different DFT functionals are known to display large differences for spin-state splittings in transition-metal complexes, and this has also been an issue for LPMOs. In this paper, we study the accuracy of DFT for spin-state splittings in superoxide, oxyl, and hydroxyl intermediates involved in LPMO turnover. As reference we employ multiconfigurational perturbation theory (CASPT2).
|
|
