“Lethal Synthesis” of Fluorocitrate by Citrate Synthase Explained through QM/MM Modeling

Kamp, Marc W. van der; McGeagh, John D.; Mulholland, Adrian J.

doi:10.1002/anie.201103260

Cited by 18 publications

(21 citation statements)

References 14 publications

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“…in making reliable predictions of regio-, Information and Modeling 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 25 stereo-and chemoselectivity. [101][102][103][104] Ryde has discussed the number of snapshots needed to give a reliable estimate of the energy in QM/MM calculations of this type, and suggested that a value of 4 kJ/mol for the standard deviation (σ) is a good convergence criterion. 105 The 6 pathways initiated from snapshots from a QM/MM MD trajectory used here ( Page 25 of 59…”

Section: Chorismate Qm Chorismate + Arg90 Qmmentioning

confidence: 99%

“…to distinguish between possible mechanisms, to identify reactive conformations 113,114 , predict the effects of mutation, reactivity of alternative substrates or analyse chemo-, stereo-or regioselectivity. [101][102][103][104] However, limitations of DFT may prevent reliable predictions even for calculations of relative barriers.…”

Section: Acs Paragon Plus Environmentmentioning

confidence: 99%

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Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution

Ranaghan

Shchepanovska

Bennie

et al. 2019

J. Chem. Inf. Model.

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Combined quantum mechanics/molecular mechanics (QM/MM) methods are increasingly widely utilized in studies of reactions in enzymes and other large systems. Here, we apply a range of QM/MM methods to investigate the Claisen rearrangement of chorismate to prephenate, in solution, and in the enzyme chorismate mutase. Using projector-based embedding in a QM/MM framework, we apply treatments up to the CCSD(T) level. We test a range of density functional QM/MM methods and QM region sizes. The results show that the calculated reaction energetics are significantly more sensitive to the choice of density functional than they are to the size of the QM region in these systems. Projector-based embedding of a wavefunction method in DFT reduced the 13 kcal/mol spread in barrier heights calculated at the DFT/MM level to a spread of just 0.3 kcal/mol, essentially eliminating dependence on the functional. Projector-based embedding of correlated ab initio methods provides a practical method for achieving high accuracy for energy profiles derived from DFT and DFT/MM calculations for reactions in condensed phases.well with the CI-NEB path and indicates that the reaction coordinate used here performs well for this reaction.Structures were taken from the corresponding solution or enzyme SCCDFTB/CHARMM22 MD stochastic boundary simulations (120 ps) of the model systems for use in adiabatic mapping calculations. For this, Jaguar 68 and Tinker 69 , linked by the interface program QoMMMa 70 , were used for QM and MM calculations, with electronic coupling between the two regions treated by including MM charges in the QM Hamiltonian.CHARMM27 Lennard-Jones parameters (for standard CHARMM27 atom types, see Table S1) were used to describe QM/MM van der Waals interactions. The QM region was treated at the hybrid density functional B3LYP/6-31G(d) level of theory, which gives a reasonably good description of the reaction. 12 The enzyme model consisted of 7077 atoms and the solution model contained 7218 atoms. The MM region comprised an approximate 25 Å radius sphere of protein and/or solvent, treated with the CHARMM27 forcefield. 71 The outer 5 Å in each case was fixed (3324 atoms fixed in the enzyme model and 3535 fixed in the solution model),with all other atoms free to move. As there is no evidence for large-scale conformational changes during the reaction, this approach should give a representative sample of reactive conformations in the enzyme. 49,51, 53,54 Each initial structure was fully optimized at the B3LYP/6-31G(d)/CHARMM27 QM/MM level, while restraining the reaction coordinate (r) to -0.5 Å with a harmonic force constant of 500 kcal/mol/Å 2 , to generate starting structures.Reaction pathways were generated by restrained optimizations in both directions along the reaction coordinate, towards the reactant and the product, in steps of 0.2 Å (0.1 Å around the TS), with both the MM and QM systems fully and consistently optimized at each step. Energy profiles were calculated from r = −2.2 Å to 2.2 Å, to identify the reactant and product mini...

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Section: Chorismate Qm Chorismate + Arg90 Qmmentioning

confidence: 99%

Section: Acs Paragon Plus Environmentmentioning

confidence: 99%

Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution

Ranaghan

Shchepanovska

Bennie

et al. 2019

J. Chem. Inf. Model.

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“…Previously, the geometries used in this study are taken from van der Kamp et al [ 11 ], where a model of the reactant complex was made by replacing acetyl-CoA with fluoroacetyl-CoA and R -malate by oxaloacetate in the crystal structure of chicken citrate synthase (PDB code: 4CSC) [ 23 ]. In this work, transition state conformations were generated from this reactant state model using QM/MM umbrella sampling at the AM1//CHARMM27 level, and subsequently, iterative QM/MM optimizations at the B3LYP/6-31+G(d)//CHARMM27 level were performed in both directions to obtain structures between rc =−1.4 Å and rc =1.4Å in 0.1 Å increments [ 11 ]. In these geometry optimizations, the side-chain of Asp375, the methylthioester portion of fluoroacetyl-CoA and oxaloacetate were chosen to be the QM region.…”

Section: Methodsmentioning

confidence: 99%

“…Van der Kamp et al [ 11 ] previously studied the enzymatic proton abstraction of fluoroacetate using high-level ab initio quantum mechanics/molecular mechanics (QM/MM) methods and concluded that E -enolate formation is favoured. In this study, geometries were optimized at the B3LYP/6-31+G(d)//CHARMM27 level and single-point energies were then calculated at the SCS-MP2 [ 12 ]/aug-cc-pVDZ//CHARMM27 level.…”

Section: Introductionmentioning

confidence: 99%

Multiscale analysis of enantioselectivity in enzyme-catalysed ‘lethal synthesis’ using projector-based embedding

et al. 2018

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The action of fluoroacetate as a broad-spectrum mammalian pesticide depends on the ‘lethal synthesis’ of fluorocitrate by citrate synthase, through a subtle enantioselective enolization of fluoroacetyl-coenzyme A. In this work, we demonstrate how a projection-based embedding method can be applied to calculate coupled cluster (CCSD(T)) reaction profiles from quantum mechanics/molecular mechanics optimized pathways for this enzyme reaction. Comparison of pro-R and pro-S proton abstraction in citrate synthase at the CCSD(T)-in-DFT//MM level yields the correct enantioselectivity. We thus demonstrate the potential of projection-based embedding for determining stereoselectivity in enzymatic systems. We further show that the method is simple to apply, eliminates variability due to the choice of density functional theory functional and allows the efficient calculation of CCSD(T) quality enzyme reaction barriers.

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“…[25] The enzyme citrate synthase catalyses a condensation between acetyl-CoA and oxaloacetate, to form citrate, a reaction that proceeds via an enol/enolate intermediate of acetyl-CoA. [26,27] For example in fatty acid biosynthesis acetyl-CoA is activated by carboxylation by acetyl-CoA carboxylase to generate malonyl-CoA when a thioester enol/ enolate reacts with carboxylated biotin in a C-C bond forming reaction. [28] In that context we can envisage that the fluorovinyl thioether (RSF¼CH 2 ) offers a potential stereoelectronic mimetic for a thioester enolate.…”

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confidence: 99%

Fluorovinyl Thioethers as Putative Steric and Electronic Thioester Enolate Mimetics: Chemoselective HF Addition to Acetylene Thioethers

2015

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Fluorovinyl thioethers are presented as a putative biomimetic surrogate for the enol/ate of a thioester. A method is explored for the preparation of fluorovinyl thioethers by treatment of acetylene thioethers with pyridinium (poly)-hydrogen fluoride. Titration with pyridine is important for the selectivity of the reaction. Without titration the corresponding gemdifluoroethyl thioethers are generated. With titration the hydrofluorination reaction can be stopped at an intermediate stage to recover the fluorovinyl thioether, which is a relatively stable functionality to purification and manipulation. Preliminary density functional theory calculations indicate that the fluorovinyl thioether motif shares a comparable steric and electronic profile to a thioester enol. A fluorovinyl thioether representing the terminus of the pantothenoyl chain of acetyl-CoA is prepared as a relevant biomimetic example.

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“Lethal Synthesis” of Fluorocitrate by Citrate Synthase Explained through QM/MM Modeling

Cited by 18 publications

References 14 publications

Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution

Projector-Based Embedding Eliminates Density Functional Dependence for QM/MM Calculations of Reactions in Enzymes and Solution

Multiscale analysis of enantioselectivity in enzyme-catalysed ‘lethal synthesis’ using projector-based embedding

Fluorovinyl Thioethers as Putative Steric and Electronic Thioester Enolate Mimetics: Chemoselective HF Addition to Acetylene Thioethers

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