Insights into enzyme catalysis from QM/MM modelling: transition state stabilization in chorismate mutase

Comparison of DFT and ab initio QM/MM methods for modelling reaction in chorismate synthase

“…The model was then solvated with a pre-equilibrated box of CHARMM-type TIP3P [23,24] water molecules and then truncated to a 25 Å sphere centered on the carbon atom C4 of EPSP (see Scheme 1). This procedure has been applied previously to model several other enzymes [19,25,26]. Combined QM/MM methods are a valuable tool in the growing area of computational enzymology [2].…”

“…FMN was modified to FMNH − and all atom types in the topology files were assigned based on the CHARMM27 parameter set [18]. The MM atomic partial charges of FMNH − and EPSP used in the initial setup of the model were based on fitting point charges to the electrostatic potential (HF/6-31G(d) CHELPG) [19,20].There are four different forms of the phosphate anion: PO 4 3− , HPO 4 2− , H 2 PO 4 − , and H 3 PO 4. Under neutral conditions, the phosphate anion could exist in either the H 2 PO 4 − or the HPO 4 2− forms, so the protonation state of the phosphate group of EPSP is an important consideration for the setup of the model system.…”

Chorismate‐Mutase‐Catalyzed Claisen Rearrangement

“…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.…”

“…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.…”

Biomolecular simulation and modelling: status, progress and prospects

“…An example is the identification of catalytic functions for the active site residues (such as a conserved proline in two flavindependent monooxygenases; Ridder et al 2000Ridder et al , 2003, investigating questions of mechanism (e.g. comparing and differentiating between alternative proposed mechanisms; van der Kamp et al 2008), and suggesting and testing catalytic principles (such as the possible contribution of conformational effects and transitionstate stabilization in chorismate mutase; Lyne et al 1995;Ranaghan et al 2003Marti et al 2004;Claeyssens et al 2005;Guimaraes et al 2005). Even for this apparently simple enzyme reaction (a Claisen rearrangement), there are lively current debates on the origin of catalysis.…”