Origin Of Catalysis Research Articles

Origins of Catalysis in Non-Heme Fe(II)/2-Oxoglutarate-Dependent Histone Lysine Demethylase KDM4A with Differently Methylated Histone H3 Peptides.

Histone lysine demethylase 4A (KDM4A), a non-heme Fe(II)/2-oxoglutarate (2OG) dependent oxygenase that catalyzes the demethylation of tri-methylated lysine residues at the 9, 27, and 36 positions of histone H3 (H3K9me3, H3K27me3, and H3K36me3). These methylated residues show contrasting transcriptional roles; therefore, understanding KDM4A's catalytic mechanisms with these substrates is essential to explain the factors that control the different sequence-dependent demethylations. In this study, we use molecular dynamics (MD)-based combined quantum mechanics/molecular mechanics (QM/MM) methods to investigate determinants of KDM4A catalysis with H3K9me3, H3K27me3 and H3K36me3 substrates. In KDM4A-H3(5-14)K9me3 and KDM4A-H3(23-32)K27me3 ferryl complexes, the O-H distance positively correlates with the activation barrier of the rate-limiting step, however in the KDM4A-H3(32-41)K36me3, no direct one-to-one relationship was found implying that the synergistic effects between the geometric parameters, second sphere interactions and the intrinsic electric field contribute for the effective catalysis for this substrate. The intrinsic electric field along the Fe-O bond changes between the three complexes and shows a positive correlation with the HAT activation barrier, suggesting that modulating electric field can be used for fine engineering KDM catalysis with a specific substrate. The results reveal how KDM4A uses a combination of strategies to enable near equally efficient demethylation of different H3Kme3 residues.

Cyclopentadiene dimerization in cucurbiturils: Origin of catalysis, dynamics and solvent effect

Cucurbit[7]uril (CB7) was recently identified as an efficient supramolecular catalyst for the challenging cyclopentadiene (CPD) dimerization. However, it remains unclear how host–guest interactions and solvent modulate the reaction mechanism and dynamics, especially the key factors controlling the catalytic effect of cucurbiturils. Herein, we computationally investigated the reaction profiles and dynamics of CPD dimerization confined in CB7 and CB8 in the gas phase and the implicit water environment. Our results revealed that water changes the alignment of the CPD molecular plane from the preferred parallel orientation in the gas phase to a perpendicular orientation towards the principal axis of CB7 during the reaction. We emphasized the importance of the host having a comparable or enhanced affinity with the guest in the transition state compared to that in the reactant complex in order to achieve excellent catalysis. Our detailed analysis demonstrated that for CPD dimerization in CB7, the largest contribution (∼65 %) to catalysis is the formation of a thermodynamically stable reactant complex, with the remaining contribution mainly from transition state entropic stabilization. The inferior performance of CB8 can be largely explained by electronic destabilization of the transition state owing to the reduced host–guest interactions in the transition state. Born-Oppenheimer trajectory simulations revealed that CB7 stabilizes the entropic intermediate with an increasing ratio of dynamically stepwise trajectories. This study will enrich our understanding of how reactions obtain enhancement and occur in a confined environment.

The Origin of Catalysis and Regioselectivity of Lewis Acid-Catalyzed Diels-Alder Reactions with Tropone.

We have studied the uncatalyzed and Lewis acid (LA)-catalyzed cycloaddition reaction between tropone and 1,1-dimethoxyethene using dispersion-corrected relativistic density functional theory (DFT). The LA catalysts BF3, B(C6H5)3, and B(C6F5)3 efficiently accelerate both the competing [4+2] and [8+2] cycloaddition reactions by lowering the activation barrier up to 12 kcal mol-1 compared to the uncatalyzed reaction. Our study reveals that the LA catalyst promotes both cycloaddition reaction pathways by LUMO-lowering catalysis and demonstrates that Pauli-lowering catalysis is not always the operative catalytic mechanism in cycloaddition reactions. Judicious choice of the LA catalyst can effectively impart regiocontrol of the cycloaddition: B(C6H5)3 furnishes the [8+2] adduct while B(C6F5)3 yields the [4+2] adduct. We discovered that the regioselectivity shift finds its origin in the ability of the LA to absorb distortion by adopting a trigonal pyramidal geometry around the boron atom.

Origin of Catalysis by Nitroalkane Oxidase.

The rate of proton abstraction of the carbon acid nitroethane by Asp402 is accelerated by a factor of 108 in the enzyme nitroalkane oxidase (NAO) relative to that by the organic base acetate ion in water. The Cα proton of nitroalkanes is known to exhibit an abnormal correlation between its acidity strength and the rate of deprotonation, with an unusually slow rate of deprotonation in water. This work examines the origin of NAO catalysis, revealing that the rate enhancement by the enzyme is due to transition-state stabilization, restoring the normal behavior of the linear free energy relationship of Bronsted acids. Interestingly, NAO employs the ubiquitous cofactor flavin adenosine diphosphate (FAD) to perform the subsequent oxidation. Does the FAD cofactor also affect the catalytic rate of the initial proton transfer process of the overall nitroalkane oxidation? Classical molecular dynamics and path-integral simulations using a reaction-specific combined quantum mechanics/molecular mechanics (QM/MM) approach were carried out to obtain the free energy reaction profiles, or the potentials of mean force, for the enzymatic reaction and for a model reaction in aqueous solution, as well as for the 2'-deoxy-FAD co-factor-modified NAO. Free energy perturbation calculations suggest that transition-state stabilization of the reactive fragment is the primary cause of the catalytic effect. It is found that the FAD cofactor plays a crucial role in increasing the Cα proton acidity, via specific hydrogen bonding and π-stacking interactions, although these factors have a smaller effect on the enhancement of the rate of deprotonation. Model QM calculations of the π-stacking complexes between the FAD isoalloxazine ring and the neutral and anionic nitroethane, respectively, reveal that the anionic π-stacking complex is more stable than the neutral one by 15.7 kcal/mol, and a net π-stacking energy of 17.3 kcal/mol is obtained. Hence, the isoalloxazine ring, in addition to serving as a very potent oxidizing agent via the formation of covalent intermediate structures, is able to exert a considerable amount of catalytic effect through noncovalent π-stacking interactions.

Origin of Catalysis and Selectivity in Lewis Acid-Promoted Diels-Alder Reactions Involving Vinylazaarenes as Dienophiles.

The poorly understood factors controlling the catalysis and selectivity in Lewis acid-promoted Diels–Alder cycloaddition reactions involving vinylazaarenes as dienophiles have been quantitatively explored in detail by means of computational methods. With the help of the activation strain model and the energy decomposition analysis methods, it is found that the remarkable acceleration induced by the catalysis is mainly due to a significant reduction of the Pauli repulsion between the key occupied π-molecular orbitals of the reactants and not due to the proposed stabilization of the lowest unoccupied molecular orbital (LUMO) of the dienophile. This computational approach has also been helpful to understand the reasons behind the extraordinary regio- and diastereoselectivity observed experimentally. The insight gained in this work allows us to predict even more reactive vinylazaarene dienophiles, which may be useful in organic synthesis.

Insights on the Origin of Catalysis on Glycine N-Methyltransferase from Computational Modeling.

The origin of enzyme catalysis remains a question of debate despite much intense study. We report a QM/MM theoretical study of the SN2 methyl transfer reaction catalyzed by a glycine N-methyltransferase (GNMT) and three mutants to test whether recent experimental observations of rate-constant reductions and variations in inverse secondary α-3H kinetic isotope effects (KIEs) should be attributed to changes in the methyl donor-acceptor distance (DAD): Is catalysis due to a compression effect? Semiempirical (AM1) and DFT (M06-2X) methods were used to describe the QM subset of atoms, while OPLS-AA and TIP3P classical force fields were used for the protein and water molecules, respectively. The computed activation free energies and KIEs are in good agreement with experimental data, but the mutations do not meaningfully affect the DAD: Compression cannot explain the experimental variations on KIEs. On the contrary, electrostatic properties in the active site correlate with the catalytic activity of wild type and mutants. The plasticity of the enzyme moderates the effects of the mutations, explaining the rather small degree of variation in KIEs and reactivities.

Valence bond and enzyme catalysis: a time to break down and a time to build up.

Understanding enzyme catalysis and developing ability to control of it are two great challenges in biochemistry. A few successful examples of computational-based enzyme design have proved the fantastic potential of computational approaches in this field, however, relatively modest rate enhancements have been reported and the further development of complementary methods is still required. Herein we propose a conceptually simple scheme to identify the specific role that each residue plays in catalysis. The scheme is based on a breakdown of the total catalytic effect into contributions of individual protein residues, which are further decomposed into chemically interpretable components by using valence bond theory. The scheme is shown to shed light on the origin of catalysis in wild-type haloalkane dehalogenase (wt-DhlA) and its mutants. Furthermore, the understanding gained through our scheme is shown to have great potential in facilitating the selection of non-optimal sites for catalysis and suggesting effective mutations to enhance the enzymatic rate.

Regional Electrophilic and Nucleophilic Fukui Functions Efficiently Highlight the Lewis Acidic/Basic Regions in Ionic Liquids

The origin of catalysis and selectivity induced by room temperature ionic liquids in several organic reactions has putatively been associated with the concept of cation effect (hydrogen bond donor ability of the ionic liquids) or anion effect (hydrogen bond accepting ability of the ionic liquids). We show that there may be cases where this a priori classification may not be correctly assigned. Cations may concentrate both Lewis acidity and basicity functions in one fragment of the ionic liquid: an effect we tentatively call bifunctional distribution of the molecular Lewis acidity/basicity. Bifunctionality on the cation is however anion dependent through electronic polarization effects. The molecular distribution of the Lewis acidity/basicity may simply be assessed by evaluating the regional Fukui function within a reference ion pair structure. The model is tested for a set of nine ionic liquids based on the 1-butyl-3-methylimidazolium cation commonly used as solvent to run organic reactions.

From Thermodynamic States to Biological Function by Einstein's Approach to Statistical Physics

Einstein founded statistical physics on an important generalization of the Boltzmann principle: Einstein's reversion, where not the model but the law of entropy is placed first. The advantage is that it assures the 2nd Law and requires no model assumptions. In particular, the existence of a complete molecular mechanism is not necessary. However, if the empirical behavior of a system is known, the entropy and the corresponding probability of the thermodynamic states can be directly derived. With his approach Einstein successfully explained Brownian motion, wave-particle dualism, quantum transitions as well as the Bose-Einstein condensation. Impossible to find in any textbook, we outline Einstein's approach and apply it to soft interfaces. The introduction of their proper entropy potential, its first, and its second derivatives predicts interfacial nonequilibrium excitation, propagation, and fluctuations, respectively. Experimental observations of the phenomenology of the membrane susceptibilities allow quantitative predictions. The propagation of waves as well as the existence of channel-like current fluctuations are experimentally confirmed and compared to measurements on living systems. Finally, we present experiments that confirm Einstein's approach to the interfacial reaction coordinate. Here the phenomenology of the system is derived from a proper entropy law even though hidden from direct observation. Not structure of molecules but entropy of the aqueous interfaces turns out to be the origin of catalysis and the associated surprising increase in reaction rate. Simultaneous specificity and activity appears now predictable and no more paradox. The theory derived from K.K. in 1999 is briefly outlined and confirmed in experiments on Acetylcholinesterases incorporated in lipid monolayers. Since enzyme activity is controlled from remote by these continuous layers, our results predict the ubiquitous, integrative action in biology of the excitable hydration interface.

ChemInform Abstract: Asymmetric Catalysis of Aldol Reactions with Chiral Lewis Bases

In an extension of studies both on the stereochemical course of the aldol addition and on Lewis-base-catalyzed allylation reactions, we have invented a new Lewis-base-catalyzed asymmetric aldol addition. This Account outlines the conceptual development, the identification of design criteria, and the underlying principles for such a process. The reduction of these elements to practice in the demonstration of enantioselective aldol additions of trichlorosilyl enolates catalyzed by chiral phosphoramides is also presented. From a combination of stereochemical, kinetic, and structural studies, an intruiging mechanistic hypothesis is forwarded that explains the origin of catalysis and diastereoselectivity.

Isotope Effect, Mechanism, and Origin of Catalysis in the Decarboxylation of Mandelylthiamin

The mechanism of decarboxylations in water and the catalysis of mandelylthiamin (MTh) decarboxylation by pyridinium ions is explored. It has been recently proposed that a decarboxylation step forming an intermediate molecule/CO(2) pair is reversible and that pyridinium ions catalyze the MTh decarboxylation by trapping the intermediate, preventing reversion to MTh. A calculation of the barrier for the back reaction goes against this proposal, as the diffusional separation of CO(2) would be on the order of 10,000 times faster. A comparison of predicted and experimental isotope effects for a series of decarboxylations including the MTh reaction shows in each case the absence of significant reversibility of the decarboxylation step. An alternative origin of the pyridinium catalysis of decarboxylation is proposed, based on the formal binding of the pyridinium ions to the decarboxylation transition state.

Origins of catalysis by computationally designed retroaldolase enzymes

We have investigated recently reported computationally designed retroaldolase enzymes with the goal of understanding the extent and the origins of their catalytic power. Direct comparison of the designed enzymes to primary amine catalysts in solution revealed a rate acceleration of 10(5)-fold for the most active of the designed retroaldolases. Through pH-rate studies of the designed retroaldolases and evaluation of a Brønsted correlation for a series of amine catalysts, we found that lysine pK(a) values are shifted by 3-4 units in the enzymes but that the catalytic contributions from the shifted pK(a) values are estimated to be modest, about 10-fold. For the most active of the reported enzymes, we evaluated the catalytic contribution of two other design components: a motif intended to stabilize a bound water molecule and hydrophobic substrate binding interactions. Mutational analysis suggested that the bound water motif does not contribute to the rate acceleration. Comparison of the rate acceleration of the designed substrate relative to a minimal substrate suggested that hydrophobic substrate binding interactions contribute around 10(3)-fold to the enzymatic rate acceleration. Altogether, these results suggest that substrate binding interactions and shifting the pK(a) of the catalytic lysine can account for much of the enzyme's rate acceleration. Additional observations suggest that these interactions are limited in the specificity of placement of substrate and active site catalytic groups. Thus, future design efforts may benefit from a focus on achieving precision in binding interactions and placement of catalytic groups.

Comparative Computational Analysis of Different Active Site Conformations and Substrates in a Chalcone Isomerase Catalyzed Reaction

Chalcone isomerase catalyzes the transformation of chalcones to flavanones. We present a computational study of the rate-limiting chemical step, an intramolecular Michael addition of a 2'-oxyanion to the alpha,beta-double bound. By using quantum mechanical/molecular mechanical hybrid methods we traced the free-energy profiles associated with the reaction of two different substrates (chalcone and 6'-deoxychalcone) in two different conformations of the active site that are described in the different crystallographic structures available. We have obtained significant differences (about 4 kcal/mol) in the free-energy barriers calculated for the two active sites. According to our results, the active site conformation with larger catalytic power presents a positively charged lysine residue much closer to the substrate than the other. Complementary electronic and electrostatic analysis shows that the charge is transferred from the 2'-oxyanion to the beta-carbon atom. Interactions of the environment with these two atoms are essential to understand the differences between both active sites and also the origin of catalysis in this enzyme.

Nornicotine aqueous aldol reactions: synthetic and theoretical investigations into the origins of catalysis.

The recent discovery that nornicotine 1, a minor nicotine metabolite, can catalyze the aldol reaction under physiologically relevant conditions has initiated research efforts into the potential chemical roles of nicotine metabolites. Herein, we disclose studies aimed at determining the origin and thus mechanism of the nornicotine-catalyzed aqueous aldol reaction. Conformationally constrained compounds designed to mimic the low-energy conformations of nornicotine were synthesized and tested for aldol catalysis; however, none showed rate enhancements on par with nornicotine. To further explore the mechanism of this process, a density functional theory (DFT) study was performed by using a variety of compounds previously tested for catalysis. These in silico studies have uncovered an unprecedented mechanistic subtlety of aqueous aldol reactions. Unlike the single transition state model observed for aldol reactions in organic solvent, the nornicotine-catalyzed reaction in water proceeds via a two-step mechanism in which a water molecule is utilized in both steps and a stable intermediate is generated. In total, these studies validate the proposed enamine-based mechanism of nornicotine-catalyzed aqueous aldol reactions and also provide the basis for future studies into the stereoelectronic nature of individual catalyst structures.

Antibody-Catalyzed Oxy-Cope Rearrangement: Mechanism and Origins of Catalysis and Stereoselectivity from DFT Quantum Mechanics and Flexible Docking

Density functional theory using B3LYP and flexible ligand docking methods were used to investigate the complete potential surface for the uncatalyzed and the AZ28 antibody-catalyzed oxy-Cope reaction of 2,5-diaryl-1,5-hexadien-3-ol derivatives. The reaction mechanism is stepwise, involving a cyclohexane diyl intermediate. Theoretical deuterium isotope effects match well with those from experiment. Gas-phase transition structures show mixed preferences for the axial vs equatorial hydroxyl group, while solvation favors the axial isomer. Specific phenyl group conformations are shown to be critical to transition-state stabilization (by up to 15 kcal/mol), and the effective conformation is not that found in the hapten used to generate the germline and affinity-matured AZ28 catalytic antibodies. Docking studies support greater transition-state binding than reactant binding. Docking studies also predict the S stereoselectivity of mature AZ28 and suggest that binding modes quite different from those of the hapten might play a role in catalysis, with specific focus on ligand hydrogen bonding to Asp(H101).

ChemInform Abstract: Chemical Design Surfaces for Active Solid Catalysts

Publisher Summary This chapter focuses on the chemical design surfaces for active solid catalysts that can be regarded as a promising and scientific way to prepare well-defined active surfaces with excellent catalytic properties as well as to elucidate reaction mechanisms, including dynamic changes of active sites. These are new generation of catalysts resulting from scientific development at the boundary between homogeneous and heterogeneous chemistry. The use of such chemically and structurally controllable surface systems, rather than the more conventional supported catalysts with heterogeneous metal centers, can lead to novel information on the origins of catalysis. Once the essential processes of activity, selectivity, and specificity have been identified, it should be possible to incorporate this knowledge into the rational synthesis of practical catalysts that are deliberately tailored for specific reaction chemistries. Chemical surface design has strategic advantages in the synthesis of catalysts with novel and desired surface structures and compositions, and in the elucidation of heterogeneous catalysis on a molecular level.