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Träfflista för sökning "WFRF:(Ryde Ulf) ;spr:eng;pers:(Cao Lili)"

Sökning: WFRF:(Ryde Ulf) > Engelska > Cao Lili

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1.
  • Cao, Lili, et al. (författare)
  • Does the crystal structure of vanadium nitrogenase contain a reaction intermediate? Evidence from quantum refinement
  • 2020
  • Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 25:6, s. 847-861
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract: Recently, a crystal structure of V-nitrogenase was presented, showing that one of the µ2 sulphide ions in the active site (S2B) is replaced by a lighter atom, suggested to be NH or NH2, i.e. representing a reaction intermediate. Moreover, a sulphur atom is found 7 Å from the S2B site, suggested to represent a storage site for this ion when it is displaced. We have re-evaluated this structure with quantum refinement, i.e. standard crystallographic refinement in which the empirical restraints (employed to ensure that the final structure makes chemical sense) are replaced by more accurate quantum–mechanical calculations. This allows us to test various interpretations of the structure, employing quantum–mechanical calculations to predict the ideal structure and to use crystallographic measures like the real-space Z-score and electron-density difference maps to decide which structure fits the crystallographic raw data best. We show that the structure contains an OH−-bound state, rather than an N2-derived reaction intermediate. Moreover, the structure shows dual conformations in the active site with ~ 14% undissociated S2B ligand, but the storage site seems to be fully occupied, weakening the suggestion that it represents a storage site for the dissociated ligand. Graphic abstract: [Figure not available: see fulltext.]
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2.
  • Cao, Lili, et al. (författare)
  • Extremely large differences in DFT energies for nitrogenase models
  • 2019
  • Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 21:5, s. 2480-2488
  • Tidskriftsartikel (refereegranskat)abstract
    • Nitrogenase is the only enzyme that can cleave the triple bond in N2, making nitrogen avaiable for other organisms. It contains a complicated MoFe7S9C(homocitrate) cluster in its active site. Many computational studies with density-functional theory (DFT) of the nitrogenase enzyme have been presented, but they do not show any consensus-they do not even agree where the first four protons should be added, forming the central intermediate E4. We show that the prime reason for this is that different DFT methods give relative energies that differ by almost 600 kJ mol-1 for different protonation states. This is 4-30 times more than what is observed for other systems. The reason for this is that in some structures, the hydrogens bind to sulfide or carbide ions as protons, whereas in other structures they bind to the metals as hydride ions, changing the oxidation state of the metals, as well as the Fe-C, Fe-S and Fe-Fe distances. The energies correlate with the amount of Hartree-Fock exchange in the method, indicating a variation in the amount of static correlation in the structures. It is currently unclear which DFT method gives the best results for nitrogenase. We show that non-hybrid DFT functionals and TPSSh give the most accurate structures of the resting active site, whereas B3LYP and PBE0 give the best H2 dissociation energies. However, no DFT method indicates that a structure of E4 with two bridging hydride ions is lowest in energy, as spectroscopic experiments indicate.
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3.
  • Cao, Lili, et al. (författare)
  • Geometry and Electronic Structure of the P-Cluster in Nitrogenase Studied by Combined Quantum Mechanical and Molecular Mechanical Calculations and Quantum Refinement
  • 2019
  • Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 58:15, s. 9672-9690
  • Tidskriftsartikel (refereegranskat)abstract
    • We have studied the geometry and electronic structure of the P-cluster in nitrogenase in four oxidation states: PN, P1+, P2+, and P3+. We have employed combined quantum mechanical and molecular mechanical (QM/MM) calculations, using two different density-functional theory methods, TPSS and B3LYP. The calculations confirm that the side chain of Ser-188 is most likely deprotonated in the partly oxidized P1+ state, thereby forming a bond to Fe6. Likewise, the backbone amide group of Cys-88 is deprotonated in the doubly oxidized P2+ state, forming a bond to Fe5. The calculations also confirm the two conformations of the P-cluster in the atomic-resolution crystal structure of the enzyme, representing the PN and P2+ states, but show that the finer differences between the two structures are not fully reflected in the crystal structure, because the coordinates of only two atoms differ between the two conformations. However, the recent crystal structure of the P1+ state seems to be of lower quality with many dubious Fe-Fe and Fe-S distances. Quantum refinement of this structure indicates that it is a mixture of the P1+ and P2+ states but confirms that the side chain of Ser-188 is most likely deprotonated in both states. TPSS gives structures that are appreciably closer to the crystal structures than does B3LYP. In addition, we have studied all 16-48 possible broken-symmetry states of the four oxidation states of the P-cluster with DFT in the one or two observed spin states. For the reduced PN state, we can settle the most likely state from the calculated energies and geometries. However, for the more oxidized states there are large differences in the predictions obtained with the two DFT methods.
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4.
  • Cao, Lili, et al. (författare)
  • Influence of the protein and DFT method on the broken-symmetry and spin states in nitroge
  • 2018
  • Ingår i: International Journal of Quantum Chemistry. - : Wiley. - 0020-7608. ; 118, s. 1-1
  • Tidskriftsartikel (refereegranskat)abstract
    • The enzyme nitrogenase contains a complicated MoFe7CS9 cofactor with 35 possible broken- symmetry (BS) states. We have studied how the energies of these states depend on the geometry, the surrounding protein, the DFT functional and the basis set, studying the resting state, a one- electron reduced state and a protonated state. We find that the effect of the basis set is small, up to 11 kJ/mol. Likewise, the effect of the surrounding protein is restricted, up to 10 and 7 kJ/mol for the electrostatic and van der Waals energy terms. Single-point energies calculated on a single geom- etry give a good correlation (R2 5 0.92-0.98) to energies calculated after geometry optimization, but some BS states may be disfavored by up to 37 kJ/mol. A change from the pure TPSS functional to the hybrid B3LYP functional may change the relative energies by up to 58 kJ/mol and the correlation between the two results is only 0.57-0.72. Both functionals agree that BS7 is the most stable BS state and that the ground spin state is the quartet for the resting state and the quintet for the reduced state. With the TPSS functional, the BS6 state is the second most stable state, always at least 21 kJ/mol less stable than the BS7 state. However, with the B3LYP functional, BS10 is the sec- ond most stable state and for the protonated state it comes close in energy. Based on these results, we suggest a procedure how to consider the 35 BS states in future investigations of the nitrogenase reaction mechanism.
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5.
  • Cao, Lili, et al. (författare)
  • N2H2 binding to the nitrogenase FeMo cluster studied by QM/MM methods
  • 2020
  • Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 25:3, s. 521-540
  • Tidskriftsartikel (refereegranskat)abstract
    • We have made a systematic combined quantum mechanical and molecular mechanical (QM/MM) investigation of possible structures of the N2 bound state of nitrogenase. We assume that N2 is immediately protonated to a N2H2 state, thereby avoiding the problem of determining the position of the protons in the cluster. We have systematically studied both end-on and side-on structures, as well as both HNNH and NNH2 states. Our results indicate that the binding of N2H2 is determined more by interactions and steric clashes with the surrounding protein than by the intrinsic preferences of the ligand and the cluster. The best binding mode with both the TPSS and B3LYP density-functional theory methods has trans-HNNH terminally bound to Fe2. It is stabilised by stacking of the substrate with His-195 and Ser-278. However, several other structures come rather close in energy (within 3–35 kJ/mol) at least in some calculations: The corresponding cis-HNNH structure terminally bound to Fe2 is second best with B3LYP. A structure with HNNH2 terminally bound to Fe6 is second most stable with TPSS (where the third proton is transferred to the substrate from the homocitrate ligand). Structures with trans-HNNH, bound to Fe4 or Fe6, or cis-HNNH bound to Fe6 are also rather stable. Finally, with the TPSS functional, a structure with cis-HNNH side-on binding to the Fe3–Fe4–Fe5–Fe7 face of the cluster is also rather low in energy, but all side-on structures are strongly disfavoured by the B3LYP method.
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6.
  • Cao, Lili, et al. (författare)
  • On the difference between additive and subtractive QM/MM calculations
  • 2018
  • Ingår i: Frontiers in Chemistry. - : Frontiers Media SA. - 2296-2646. ; 6:APR
  • Tidskriftsartikel (refereegranskat)abstract
    • 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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7.
  • Cao, Lili, et al. (författare)
  • Protonation and Reduction of the FeMo Cluster in Nitrogenase Studied by Quantum Mechanics/Molecular Mechanics (QM/MM) Calculations
  • 2018
  • Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 14:12, s. 6653-6678
  • Tidskriftsartikel (refereegranskat)abstract
    • We have performed a systematic computational study of the relative energies of possible protonation states of the FeMo cluster in nitrogenase in the E0-E4 states, i.e., the resting state and states with 1-4 electrons and protons added but before N2 binds. We use the combined quantum mechanics and molecular mechanics (QM/MM) approach, including the complete solvated heterotetrameric enzyme in the calculations. The QM system consisted of 112 atoms, i.e., the full FeMo cluster, as well all groups forming hydrogen bonds to it within 3.5 Å. It was treated with either the TPSS-D3 or B3LYP-D3 methods with the def2-SV(P) or def2-TZVPD basis sets. For each redox state, we calculated relative energies of at least 50 different possible positions for the proton, added to the most stable protonation state of the level with one electron less. We show quite conclusively that the resting E0 state is not protonated using quantum refinement and by comparing geometries to the crystal structure. The E1 state is protonated on S2B, in agreement with most previous computational studies. However, for the E2-E4 states, the two QM methods give diverging results, with relative energies that differ by over 300 kJ/mol for the most stable E4 states. TPSS favors hydride ions binding to the Fe ions. The first bridges Fe2 and Fe6, whereas the next two bind terminally to either Fe4, Fe5, or Fe6 with nearly equal energies. On the other hand, B3LYP disfavors hydride ions and instead suggests that 1-3 protons bind to the central carbide ion.
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8.
  • Cao, Lili, et al. (författare)
  • Protonation States of Homocitrate and Nearby Residues in Nitrogenase Studied by Computational Methods and Quantum Refinement
  • 2017
  • Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 121:35, s. 8242-8262
  • Tidskriftsartikel (refereegranskat)abstract
    • Nitrogenase is the only enzyme that can break the triple bond in N2 to form two molecules of ammonia. The enzyme has been thoroughly studied with both experimental and computational methods, but there is still no consensus regarding the atomic details of the reaction mechanism. In the most common form, the active site is a MoFe7S9C(homocitrate) cluster. The homocitrate ligand contains one alcohol and three carboxylate groups. In water solution, the triply deprotonated form dominates, but because the alcohol (and one of the carboxylate groups) coordinate to the Mo ion, this may change in the enzyme. We have performed a series of computational calculations with molecular dynamics (MD), quantum mechanical (QM) cluster, combined QM and molecular mechanics (QM/MM), QM/MM with Poisson-Boltzmann and surface area solvation, QM/MM thermodynamic cycle perturbations, and quantum refinement methods to settle the most probable protonation state of the homocitrate ligand in nitrogenase. The results quite conclusively point out a triply deprotonated form (net charge -3) with a proton shared between the alcohol and one of the carboxylate groups as the most stable at pH 7. Moreover, we have studied eight ionizable protein residues close to the active site with MD simulations and determined the most likely protonation states.
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9.
  • Cao, Lili, et al. (författare)
  • Putative reaction mechanism of nitrogenase after dissociation of a sulfide ligand
  • 2020
  • Ingår i: Journal of Catalysis. - : Elsevier BV. - 1090-2694 .- 0021-9517. ; 391, s. 247-259
  • Tidskriftsartikel (refereegranskat)abstract
    • We have investigated the implications of the recent crystallographic findings that the m2-bridging S2B sulfide ligand may reversibly dissociate from the active-site FeMo cluster of nitrogenase. We show with combined quantum mechanical and molecular mechanical (QM/MM) calculations that once S2B has dis- sociated, N2 may bind in that position and can be protonated to two NH3 groups by thermodynamically favourable steps. The substrate forms hydrogen bonds with two protein ligands, Gln-191 and His-195. For all steps, we have studied three possible protonation states of His-195 (protonated on either ND1, NE2 or both). We find that the thermodynamically favoured path involves an end-on NNH2 structure, a mixed side-on/end-on H2NNH structure, a side-on H2NNH2 structure, a bridging NH2 structure and a bridging NH3 structure. In all cases, His-195 seems to be protonated on the NE2 atom. Dissociation of the NH3 pro- duct is often unfavourable and requires either further reduction or protonation of the cluster or rebinding of S2B. In conclusion, our calculations show that dissociation of S2B gives rise to a natural binding and reaction site for nitrogenase, between the Fe2 and Fe6 atoms, which can support an alternating reaction mechanism with favourable energetics.
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10.
  • Cao, Lili, et al. (författare)
  • Quantum Refinement Does Not Support Dinuclear Copper Sites in Crystal Structures of Particulate Methane Monooxygenase
  • 2018
  • Ingår i: Angewandte Chemie - International Edition. - : Wiley. - 1433-7851. ; 57:1, s. 162-166
  • Tidskriftsartikel (refereegranskat)abstract
    • Particulate methane monooxygenase (pMMO) is one of the few enzymes that can activate methane. The metal content of this enzyme has been highly controversial, with suggestions of a dinuclear Fe site or mono-, di-, or trinuclear Cu sites. Crystal structures have shown a mono- or dinuclear Cu site, but the resolution was low and the geometry of the dinuclear site unusual. We have employed quantum refinement (crystallographic refinement enhanced with quantum-mechanical calculations) to improve the structure of the active site. We compared a number of different mono- and dinuclear geometries, in some cases enhanced with more protein ligands or one or two water molecules, to determine which structure fits two sets of crystallographic raw data best. In all cases, the best results were obtained with mononuclear Cu sites, occasionally with an extra water molecule. Thus, we conclude that there is no crystallographic support for a dinuclear Cu site in pMMO.
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