Can the local electric field be a descriptor of catalytic activity? A case study on chorismate mutase.
TL;DR: In this article, the local electric field (LEF) of the enzyme along the reaction axis was proposed as a descriptor for the enzymatic activity using the example of chorismate mutase in its native form and several variants (R90A, R90G, and R90K/C88S).
Abstract: The current theoretical perception of enzymatic activity is highly reliant on the determination of the activation energy of the reactions, which is often calculated using computationally demanding quantum mechanical calculations. With the ever-increasing use of bioengineering techniques that produce too many variants of the same enzyme, a fast and accurate way to study the relative efficiency of enzymes is currently in high demand. Here, we propose the local electric field (LEF) of the enzyme along the reaction axis as a descriptor for the enzymatic activity using the example of chorismate mutase in its native form and several variants (R90A, R90G, and R90K/C88S). The study shows a direct correlation between the calculated enzymatic EF and the enzymatic activity for all the complexes. MD simulations of the Michaelis complex and the transition state analog (TSA) show a stabilizing force on the TSA due to the enzymatic EF. QM/MM and QM-only DFT calculations in the presence of an external electric field (EEF) oriented along the reaction axis show that the electric field can interact with the dipole moment of the TS, thereby stabilizing it and thus lowering the activation energy.
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TL;DR: In this paper , the authors investigated the influence of ionic correlations on CO2 electroreduction and found substantial acceleration of potentialdependent CO2 reduction rates and enhancement of faradaic efficiency to CO at intermediate concentrations of 0.9 M ionic liquid in acetonitrile.
Abstract: Electric double layer formation often governs the rate and selectivity of CO2 electrochemical reduction. Ionic correlations critically define double layer properties that are essential to electrocatalytic performance, including capacitance and localization of potential gradients. However, the influence of ionic correlations on CO2 electroreduction remains unexplored. Here, we use electrochemical conversion of CO2 to CO in ionic liquid-based electrolytes to investigate how the emergence of ionic correlations with increasing ion concentration influences reaction rates and selectivity. Remarkably, we find substantial acceleration of potential-dependent CO2 reduction rates and enhancement of faradaic efficiency to CO at intermediate concentrations of 0.9 M ionic liquid in acetonitrile, a concentration regime that has not been studied previously. We find that onset potentials for CO2 reduction remain relatively unchanged at −2.01 V vs Ag/Ag+ from 0.025 M up to 1.1 M and increase to −2.04 V vs Ag/Ag+ in the limit of neat ionic liquids. Hence, the acceleration of CO2 reduction we observe originates from the amplification of potential-dependent driving forces, as opposed to changes in onset potential. Importantly, our findings are general across cocatalytic and noncatalytic ions. We propose that concentrations of maximum reactivity correspond to conditions where electric double layers exhibit the strongest screening, which would localize electric fields to stabilize polar intermediates. Our study demonstrates that tuning bulk electrostatic screening lengths via modulation of ionic clustering provides a general approach to accelerating both inner-sphere and outer-sphere electrochemical reactions.
5 citations
TL;DR: In this paper , the authors discuss the electrostatics principles that drive enzyme catalysis and its experimental verifications through vibrational Stark spectroscopy, and describe aspects of LEFs other than catalysis, i.e., induction of mechanistic crossovers, among others.
Abstract: This Mini-Review Article outlines recent advances in the study of local electric field (LEF) governed enzyme catalysis and the application of the LEF principle in synthetic catalyst design. We start by discussing the electrostatics principles that drive enzyme catalysis, and its experimental verifications through vibrational Stark spectroscopy. Subsequently, we describe aspects of LEFs other than catalysis, i.e., induction of mechanistic crossovers, among others. Here, we focus on the early work done using computational tools, along with some recent contributions. Following an in-depth discussion of the role of LEFs in enzyme catalysis, we then highlight some recent works on designed local electric fields (D-LEF) and their applications in organic synthesis. Subsequently, we turn to D-LEFs in synthetic enzymes and supramolecular systems (cf. the work by the Head-Gordon group). We end by discussing some of the software packages that have been developed to analyze local electric fields computationally. Overall, the present Mini-Review Article paints an insightful picture of the current state of the art using LEF in enzyme catalysis and its application for further bioengineering and synthetic organic frameworks in a broad perspective.
3 citations
TL;DR: The study shows that the stabilities of the enzyme complexes are well maintained in all three water models, and the OPC water model performs well for the polar active sites, while the TIP3P water model is superior for the hydrophobic site, such as CYP450BM3.
Abstract: Modeling approaches and modern simulations to investigate the biomolecular structure and function rely on various methods. Since water molecules play a crucial role in all sorts of chemistry, the accurate modeling of water molecules is vital for such simulations. In cytochrome P450 (CYP450), in particular, water molecules play a key role in forming active oxidant that ultimately performs oxidation and metabolism. In the present study, we have highlighted the behavior of the three most widely used water models─TIP3P, SPC/E, and OPC─for three different CYP450 enzymes─CYP450BM3, CYP450OleT, and CYP450BSβ─during MD simulations and QM/MM calculations. We studied the various properties, such as RMSD, RMSF, H-bond, water occupancy, and hydrogen atom transfer (HAT), using QM/MM calculations and compared them for all three water models. Our study shows that the stabilities of the enzyme complexes are well maintained in all three water models. However, the OPC water model performs well for the polar active sites, that is, in CYP450OleT and CYP450BSβ, while the TIP3P water model is superior for the hydrophobic site, such as CYP450BM3.
3 citations
TL;DR: In this article , an external electric field (ExtEF) along the Fe-O bond in the EFE·Fe(III)·OO-˙·2OG·L-Arg complex was proposed to switch EFE reactivity between L-Arg hydroxylation and ethylene generation.
Abstract: The non-heme Fe(II) and 2-oxoglutarate (2OG) dependent ethylene-forming enzyme (EFE) catalyzes both ethylene generation and L-Arg hydroxylation. Despite experimental and computational progress in understanding the mechanism of EFE, no EFE variant has been optimized for ethylene production while simultaneously reducing the L-Arg hydroxylation activity. In this study, we show that the two L-Arg binding conformations, associated with different reactivity preferences in EFE, lead to differences in the intrinsic electric field (IntEF) of EFE. Importantly, we suggest that applying an external electric field (ExtEF) along the Fe-O bond in the EFE·Fe(III)·OO-˙·2OG·L-Arg complex can switch the EFE reactivity between L-Arg hydroxylation and ethylene generation. Furthermore, we explored how applying an ExtEF alters the geometry, electronic structure of the key reaction intermediates, and the individual energy contributions of second coordination sphere (SCS) residues through combined quantum mechanics/molecular mechanics (QM/MM) calculations. Experimentally generated variant forms of EFE with alanine substituted for SCS residues responsible for stabilizing the key intermediates in the two reactions of EFE led to changes in enzyme activity, thus demonstrating the key role of these residues. Overall, the results of applying an ExtEF indicate that making the IntEF of EFE less negative and stabilizing the off-line binding of 2OG is predicted to increase ethylene generation while reducing L-Arg hydroxylation.
TL;DR: In this article , a QM/MM-based approach was proposed to evaluate the effects of the electric fields exerted by individual residues in the protein scaffold. But, the results showed that the heterogeneity of the residue electric fields and the effect of the native protein environment can be properly accounted for by this approach.
Abstract: The protein scaffolds of enzymes not only provide structural support for the catalytic center but also exert preorganized electric fields for electrostatic catalysis. In recent years, uniform oriented external electric fields (OEEFs) have been widely applied to enzymatic reactions to mimic the electrostatic effects of the environment. However, the electric fields exerted by individual residues in proteins may be quite heterogeneous across the active site, with varying directions and strengths at different positions of the active site. Here, we propose a QM/MM-based approach to evaluate the effects of the electric fields exerted by individual residues in the protein scaffold. In particular, the heterogeneity of the residue electric fields and the effect of the native protein environment can be properly accounted for by this QM/MM approach. A case study of the O-O heterolysis reaction in the catalytic cycle of TyrH shows that (1) for scaffold residues that are relatively far from the active site, the heterogeneity of the residue electric field in the active site is not very significant and the electrostatic stabilization/destabilization due to each residue can be well approximated with the interaction energy between a uniform electric field and the QM region dipole; (2) for scaffold residues near the active site, the residue electric fields can be highly heterogeneous along the breaking O-O bond. In such a case, approximating the residue electric fields as uniform fields may misrepresent the overall electrostatic effect of the residue. The present QM/MM approach can be applied to evaluate the residues' electrostatic impact on enzymatic reactions, which also can be useful in computational optimization of electric fields to boost the enzyme catalysis.
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TL;DR: In this article, a semi-empirical exchange correlation functional with local spin density, gradient, and exact exchange terms was proposed. But this functional performed significantly better than previous functionals with gradient corrections only, and fits experimental atomization energies with an impressively small average absolute deviation of 2.4 kcal/mol.
Abstract: Despite the remarkable thermochemical accuracy of Kohn–Sham density‐functional theories with gradient corrections for exchange‐correlation [see, for example, A. D. Becke, J. Chem. Phys. 96, 2155 (1992)], we believe that further improvements are unlikely unless exact‐exchange information is considered. Arguments to support this view are presented, and a semiempirical exchange‐correlation functional containing local‐spin‐density, gradient, and exact‐exchange terms is tested on 56 atomization energies, 42 ionization potentials, 8 proton affinities, and 10 total atomic energies of first‐ and second‐row systems. This functional performs significantly better than previous functionals with gradient corrections only, and fits experimental atomization energies with an impressively small average absolute deviation of 2.4 kcal/mol.
87,732 citations
TL;DR: In this article, the authors compared the Bernal Fowler (BF), SPC, ST2, TIPS2, TIP3P, and TIP4P potential functions for liquid water in the NPT ensemble at 25°C and 1 atm.
Abstract: Classical Monte Carlo simulations have been carried out for liquid water in the NPT ensemble at 25 °C and 1 atm using six of the simpler intermolecular potential functions for the water dimer: Bernal–Fowler (BF), SPC, ST2, TIPS2, TIP3P, and TIP4P. Comparisons are made with experimental thermodynamic and structural data including the recent neutron diffraction results of Thiessen and Narten. The computed densities and potential energies are in reasonable accord with experiment except for the original BF model, which yields an 18% overestimate of the density and poor structural results. The TIPS2 and TIP4P potentials yield oxygen–oxygen partial structure functions in good agreement with the neutron diffraction results. The accord with the experimental OH and HH partial structure functions is poorer; however, the computed results for these functions are similar for all the potential functions. Consequently, the discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons are also made for self‐diffusion coefficients obtained from molecular dynamics simulations. Overall, the SPC, ST2, TIPS2, and TIP4P models give reasonable structural and thermodynamic descriptions of liquid water and they should be useful in simulations of aqueous solutions. The simplicity of the SPC, TIPS2, and TIP4P functions is also attractive from a computational standpoint.
33,683 citations
TL;DR: In this paper, a method is described to realize coupling to an external bath with constant temperature or pressure with adjustable time constants for the coupling, which can be easily extendable to other variables and to gradients, and can be applied also to polyatomic molecules involving internal constraints.
Abstract: In molecular dynamics (MD) simulations the need often arises to maintain such parameters as temperature or pressure rather than energy and volume, or to impose gradients for studying transport properties in nonequilibrium MD A method is described to realize coupling to an external bath with constant temperature or pressure with adjustable time constants for the coupling The method is easily extendable to other variables and to gradients, and can be applied also to polyatomic molecules involving internal constraints The influence of coupling time constants on dynamical variables is evaluated A leap‐frog algorithm is presented for the general case involving constraints with coupling to both a constant temperature and a constant pressure bath
25,256 citations
TL;DR: An N⋅log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolutions using fast Fourier transforms.
Abstract: An N⋅log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolutions using fast Fourier transforms. Timings and accuracies are presented for three large crystalline ionic systems.
24,332 citations
TL;DR: A new density functional of the generalized gradient approximation (GGA) type for general chemistry applications termed B97‐D is proposed, based on Becke's power‐series ansatz from 1997, and is explicitly parameterized by including damped atom‐pairwise dispersion corrections of the form C6 · R−6.
Abstract: A new density functional (DF) of the generalized gradient approximation (GGA) type for general chemistry applications termed B97-D is proposed. It is based on Becke's power-series ansatz from 1997 and is explicitly parameterized by including damped atom-pairwise dispersion corrections of the form C(6) x R(-6). A general computational scheme for the parameters used in this correction has been established and parameters for elements up to xenon and a scaling factor for the dispersion part for several common density functionals (BLYP, PBE, TPSS, B3LYP) are reported. The new functional is tested in comparison with other GGAs and the B3LYP hybrid functional on standard thermochemical benchmark sets, for 40 noncovalently bound complexes, including large stacked aromatic molecules and group II element clusters, and for the computation of molecular geometries. Further cross-validation tests were performed for organometallic reactions and other difficult problems for standard functionals. In summary, it is found that B97-D belongs to one of the most accurate general purpose GGAs, reaching, for example for the G97/2 set of heat of formations, a mean absolute deviation of only 3.8 kcal mol(-1). The performance for noncovalently bound systems including many pure van der Waals complexes is exceptionally good, reaching on the average CCSD(T) accuracy. The basic strategy in the development to restrict the density functional description to shorter electron correlation lengths scales and to describe situations with medium to large interatomic distances by damped C(6) x R(-6) terms seems to be very successful, as demonstrated for some notoriously difficult reactions. As an example, for the isomerization of larger branched to linear alkanes, B97-D is the only DF available that yields the right sign for the energy difference. From a practical point of view, the new functional seems to be quite robust and it is thus suggested as an efficient and accurate quantum chemical method for large systems where dispersion forces are of general importance.
23,058 citations