Insights into Chorismate Mutase Catalysis from a Combined QM/MM Simulation of the Enzyme Reaction

Lyne, Paul; Mulholland, Adrian J.; Richards, William G.

doi:10.1021/ja00150a037

Cited by 161 publications

(211 citation statements)

References 2 publications

(2 reference statements)

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“…These observations have led to the suggestion that one possible origin of the catalysis is electrostatic interactions from the active site residues that stabilize the developing charges in the transition state (TS) and lower the activation barrier. Several computational studies [49,58,67,71,75,80] of the BsCM catalysis support the suggestion that chorismate mutase works by stabilization of transition state through electrostatic interactions from the active site residues. For instance, Lyne et al [49], Lee et al [67] and Ranaghan et al [76] performed hybrid quantum mechanical/molecular mechanical (QM/MM) studies of BsCM.…”

Section: Stabilization Of Transition State By Active Site Residuesmentioning

confidence: 73%

“…Several computational studies [49,58,67,71,75,80] of the BsCM catalysis support the suggestion that chorismate mutase works by stabilization of transition state through electrostatic interactions from the active site residues. For instance, Lyne et al [49], Lee et al [67] and Ranaghan et al [76] performed hybrid quantum mechanical/molecular mechanical (QM/MM) studies of BsCM. In a hybrid QM/ MM approach, the flexibility of a quantum mechanical description for a small number of atoms at the active site or in solution (e.g., the atoms in chorismate) is combined with the efficiency of an empirical force field representation for the bulk of the solvated system.…”

Section: Stabilization Of Transition State By Active Site Residuesmentioning

confidence: 73%

“…So both the chemical events of bond breaking and making (e.g., the change from chorismate to prephenate) as well as the effects of the environment (e.g., the reduction of activation barrier by the enzyme) could be described. Lyne et al [49], Lee et al [67] and Ranaghan et al [76] used a perturbation approach [84] based on fixed BsCM-CHAIR and BsCM-TS structures to study the contribution of each residue to the lowering of the reaction barrier in going from the CHAIR conformer to TS. In this perturbation approach, the charges on the atoms of the residue under consideration are turned off.…”

Section: Stabilization Of Transition State By Active Site Residuesmentioning

confidence: 99%

See 2 more Smart Citations

Chorismate‐Mutase‐Catalyzed Claisen Rearrangement

Guo

Rao

2007

The Claisen Rearrangement

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Section: Stabilization Of Transition State By Active Site Residuesmentioning

confidence: 73%

Section: Stabilization Of Transition State By Active Site Residuesmentioning

confidence: 73%

Section: Stabilization Of Transition State By Active Site Residuesmentioning

confidence: 99%

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Chorismate‐Mutase‐Catalyzed Claisen Rearrangement

Guo

Rao

2007

The Claisen Rearrangement

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“…From the highly polar TS structure and the electrostatic interactions observed in the crystal structure of EcCM complexed with the TSA, it has been proposed that tighter binding of TS compared with substrate (CHOR) by EcCM is responsible for the Ͼ10 6 catalytic enhancement (8,20,(25)(26)(27). The 100-fold tighter binding (K i ͞K m ϭ 100) of TSA compared with CHOR has been interpreted as being caused by TSA being a transition state analogue.…”

Section: Discussionmentioning

confidence: 99%

The mechanism of catalysis of the chorismate to prephenate reaction by the Escherichia coli mutase enzyme

Hur

Bruice

2002

Proc. Natl. Acad. Sci. U.S.A.

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T ighter binding of transition state (TS) as compared with substrate ground state (GS) is the most often used explanation for efficiency of enzymatic catalysis (1). We have initiated investigations of the dynamic structures of enzyme⅐ground state (E⅐GS) and E⅐TS to compare electrostatic and hydrophobic interactions of enzyme with GS and TS. Our goal has been to determine whether TS preferential binding over GS is (i) a tenet for all enzymes, (ii) always present but other things also contribute, or (iii) important in some enzymatic reactions but not in others. Theoretical arguments for the tenet that TS stabilization drives enzyme catalysis is based on Scheme 1. In this model, K TS is the ratio of nonenzymatic reaction rate over enzymatic reaction rate K TS ϭ k non (K m ͞k cat ). The equilibrium constant for dissociation of E⅐TS in water is generally taken as K TS . Observed from a different standpoint, Scheme 1 becomes Scheme 2 and ⌬G°K TS ϭ ⌬G NON Ϫ ⌬G kcat/Km . Thus, ⌬G°K TS is nothing more than a measure of the difference in free energies of activation for the enzymatic and nonenzymatic reaction, and this free-energy difference reflects all features of the enzymatic and nonenzymatic reactions. There is no theoretical reason to believe that K TS reflects binding affinity of TS to enzyme. On the continuum of our study, we have chosen to examine a chorismate (CHOR) mutase. In this class of enzymes, there is no direct participation of enzyme in the chemical reaction (2-4) and TS geometry in an enzyme-catalyzed reaction is similar to TS in a noncatalyzed reaction (5, 6). These features enable us to directly compare the binding modes of enzyme with TS and GS (7).CHOR mutases increase the rate of the Claisen rearrangement of CHOR to prephenate (Scheme 3) by greater than 10 6 -fold relative to the reaction in water (8). The crystal structures of CHOR mutase from Bacillus subtilis (BsCM) (4), Escherichia coli (EcCM) (9), and yeast (10) have been solved. The majority of studies on CHOR mutase have focused on BsCM.A hydrogen bond between a negatively charged glutamate and the hydroxyl group of CHOR is critical to the reaction in BsCM (11) but not in EcCM. There is only one arginine holding the carboxylate at the side chain of CHOR in BsCM, whereas both carboxylates of CHOR are strongly held by two arginines in EcCM. The extensive exposure to the solvent and versatile mode of hydrogen bonds observed in the active site of BsCM show a great counterpoint to the extremely stable hydrogen bonding network observed in the EcCM active site. The active site of EcCM is buried in the protein and allows little solvent accessibility. The BsCM catalyzed reaction is slowed when solvent viscosity is increased, whereas the EcCM catalyzed reaction is not (12). For BsCM, kinetic isotope-effect experiments show the rate-determining step is largely in the chemical rearrangement (13), whereas in EcCM it is not so under the same V max ͞K m condition (14). The two enzymes differ in structures of E⅐CHOR complex and kinetic handling of the pericy...

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“…In this treatment we divide the solvent into two regions. In the first region (region I), we convert the N ext solvent atoms to m×N ext external charges (scaled by 1/m), while in region II, we represent the average solvent field coming from N-N ext solvent molecules, by two point charges (q and −q) using: (12) where E O is electric field gradient at point O (the geometrical center of QM system) and OR is pointing along E O to charge q.…”

Section: Methodsmentioning

confidence: 99%

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

et al. 2008

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Reliable studies of enzymatic reactions by combined quantum mechanical /molecular mechanics (QM(ai)/MM) approaches, with an ab initio description of the quantum region, presents a major challenge to computational chemists. The main problem is the need for very large computer time to evaluate the QM energy, which in turn makes it extremely challenging to perform proper configurational sampling. One of the most obvious options for accelerating QM/MM simulations is the use of an average solvent potential. In fact the idea of using an average solvent potential is rather obvious and has implicitly been used in Langevin dipole / QM calculations. However, in the case of explicit solvent models the practical implementations are more challenging and the accuracy of the averaging approach has not been validated. The present study introduces the average effect of the fluctuating solvent charges by using equivalent charge distributions, which are updated every m steps. Several models are evaluated in terms of the resulting accuracy and efficiency. The most effective model divides the system into an inner region with N explicit solvent atoms and an external region with two effective charges. Different models are considered in terms of the division of the solvent system and the update frequency. Another key element of our approach is the use of the free energy perturbation (FEP) and/or linear response approximation (LRA) treatments that guarantees the evaluation of the rigorous solvation free energy. Special attention is paid to the convergence of the calculated solvation free energies and the corresponding solute polarization. The performance of the method is examined by evaluating the solvation of a water molecule and a formate ion in water and also the dipole moment of water in water solution. Remarkably, it is found that different averaging procedures eventually converge to the same value but some protocols provide optimal ways of obtaining the final QM(ai)/MM converged results. The current method can provide computational time saving of 1000 for properly converging simulations relative to calculations that evaluate the QM(ai)/MM energy every time step. A specialized version of our approach that starts with a classical FEP charging and then evaluates the free energy of moving from the classical potential to the QM/ MM potential appears to be particularly effective. This approach should provide a very powerful tool for QM(ai)/MM evaluation of solvation free energies in aqueous solutions and proteins.

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Insights into Chorismate Mutase Catalysis from a Combined QM/MM Simulation of the Enzyme Reaction

Cited by 161 publications

References 2 publications

Chorismate‐Mutase‐Catalyzed Claisen Rearrangement

Chorismate‐Mutase‐Catalyzed Claisen Rearrangement

The mechanism of catalysis of the chorismate to prephenate reaction by the Escherichia coli mutase enzyme

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

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