Facilitate Proton Transfer Research Articles

ChemInform Abstract: Hydrogen and Dihydrogen Bonds in the Reactions of Metal Hydrides

AbstractReview: 362 refs.

Electrogenic steps of light-driven proton transport in ESR, a retinal protein from Exiguobacterium sibiricum

A retinal protein from Exiguobacterium sibiricum (ESR) functions as a light-driven proton pump. Unlike other proton pumps, it contains Lys96 instead of a usual carboxylic residue in the internal proton donor site. Nevertheless, the reprotonation of the Schiff base occurs fast, indicating that Lys96 facilitates proton transfer from the bulk. In this study we examined kinetics of light-induced transmembrane electrical potential difference, ΔΨ, generated in proteoliposomes reconstituted with ESR. We show that total magnitude of ΔΨ is comparable to that produced by bacteriorhodopsin but its kinetic components and their pH dependence are substantially different. The results are in agreement with the earlier finding that proton uptake precedes reprotonation of the Schiff base in ESR, suggesting that Lys96 is unprotonated in the initial state and gains a proton transiently in the photocycle. The electrogenic phases and the photocycle transitions related to proton transfer from the bulk to the Schiff base are pH dependent. At neutral pH, they occur with τ 0.5ms and 4.5ms. At alkaline pH, the fast component ceases and Schiff base reprotonation slows. At pH8.4, a spectrally silent electrogenic component with τ 0.25ms is detected, which can be attributed to proton transfer from the bulk to Lys96. At pH5.1, the amplitude of ΔΨ decreases 10 fold, reflecting a decreased yield and rate of proton transfer, apparently from protonation of the acceptor (Asp85-His57 pair) in the initial state. The features of the photoelectric potential generation correlate with the ESR structure and proposed mechanism of proton transfer.

Relative Binding Affinities of Monolignols to Horseradish Peroxidase.

Monolignol binding to the peroxidase active site is the first step in lignin polymerization in plant cell walls. Using molecular dynamics, docking, and free energy perturbation calculations, we investigate the binding of monolignols to horseradish peroxidase C. Our results suggest that p-coumaryl alcohol has the strongest binding affinity followed by sinapyl and coniferyl alcohol. Stacking interactions between the monolignol aromatic rings and nearby phenylalanine residues play an important role in determining the calculated relative binding affinities. p-Coumaryl and coniferyl alcohols bind in a pose productive for reaction in which a direct H-bond is formed between the phenolic -OH group and a water molecule (W2) that may facilitate proton transfer during oxidation. In contrast, in the case of sinapyl alcohol there is no such direct interaction, the phenolic -OH group instead interacting with Pro139. Since proton and electron transfer is the rate-limiting step in monolignol oxidation by peroxidase, the binding pose (and thus the formation of near attack conformation) appears to play a more important role than the overall binding affinity in determining the oxidation rate.

Hydrogen and Dihydrogen Bonds in the Reactions of Metal Hydrides.

The dihydrogen bond-an interaction between a transition-metal or main-group hydride (M-H) and a protic hydrogen moiety (H-X)-is arguably the most intriguing type of hydrogen bond. It was discovered in the mid-1990s and has been intensively explored since then. Herein, we collate up-to-date experimental and computational studies of the structural, energetic, and spectroscopic parameters and natures of dihydrogen-bonded complexes of the form M-H···H-X, as such species are now known for a wide variety of hydrido compounds. Being a weak interaction, dihydrogen bonding entails the lengthening of the participating bonds as well as their polarization (repolarization) as a result of electron density redistribution. Thus, the formation of a dihydrogen bond allows for the activation of both the MH and XH bonds in one step, facilitating proton transfer and preparing these bonds for further transformations. The implications of dihydrogen bonding in different stoichiometric and catalytic reactions, such as hydrogen exchange, alcoholysis and aminolysis, hydrogen evolution, hydrogenation, and dehydrogenation, are discussed.

Facilitated Lewis Acid Transfer by Phospholipids at a (Water|CHCl3) Liquid|Liquid Interface toward Biomimetic and Energy Applications

Proton and metal ion interaction with phospholipids are of considerable interest to biological applications (e.g., chemical communication, drug transport, etc.). Herein, H+ and Li+ coordination to a typical phospholipid are examined electrochemically at the water|chloroform microinterface, which reveals two coordination stoichiometries toward protons that were thermodynamically quantified using cyclic voltammetry. The thermodynamics of phospholipid facilitated proton transfer are further confirmed through Comsol Multiphysics simulations. Insight into H+–phospholipid coordination/interaction has valuable implications toward cellular communication (such as vesicle systems that mimic living cells) and vesicle microreactor synthetic applications; however, the utility of the H+/phospholipid coupled water|organic solvent system is exemplified herein toward the batch generation of solar fuels through shake-flask experiments.

Theoretical investigation of proton-transfer in different membranes for PEMFC applications in low humidity conditions

A comparative theoretical study was performed to explore the effect of polymer backbone on the proton exchange in different sulfonated membranes such as poly(phenylene oxide), poly(benzimidazole), polyimide, poly(oxadiazole) and Nafion 117 at low hydration state. Geometry optimization of the membranes in the presence of different numbers of water molecules (1–3 water molecules) revealed that proton dissociation energies and hydrogen bond interactions (which are of critical importance in proton transfer) depend strongly on the polymer structure’s functional groups. When the polymer dose not stabilize hydronium ion or sulfonate anion, water molecules are arranged around sulfonate group and form a two-ring hydrogen bonded structure; in addition, this polymer showed high proton transfer energy (25.0, 27.2 and 19.4kcal/mol for sulfonated poly(phenylene oxide), sulfonated meta-poly(benzimidazole) and Nafion 117). Theoretical studies also demonstrated that the position of sulfonate group and functional groups in the polymer structure was effective in proton dissociation. In this regard, proton transfer energy for para-sulfonated poly(benzimidazole) was about 17.7kcal/mol less than sulfonated meta-poly(benzimidazole); this energy difference could be attributed to the imidazolium cation formation and its stabilizing effect on sulfonate anion. The molecular graphs for sulfonated poly(oxadiazole) indicated that, although this polymer had the highest proton transfer energy among the polymers, it formed a continuous and strong hydrogen bond chain that facilitated proton transfer by hopping mechanism.

Methanethiol Binding Strengths and Deprotonation Energies in Zn(II)-Imidazole Complexes from M05-2X and MP2 Theories: Coordination Number and Geometry Influences Relevant to Zinc Enzymes.

Zn(II) is used in nature as a biocatalyst in hundreds of enzymes, and the structure and dynamics of its catalytic activity are subjects of considerable interest. Many of the Zn(II)-based enzymes are classified as hydrolytic enzymes, in which the Lewis acidic Zn(II) center facilitates proton transfer(s) to a Lewis base, from proton donors such as water or thiol. This report presents the results of a quantum computational study quantifying the dynamic relationship between the zinc coordination number (CN), its coordination geometry, and the thermodynamic driving force behind these proton transfers originating from a charge-neutral methylthiol ligand. Specifically, density functional theory (DFT) and second-order perturbation theory (MP2) calculations have been performed on a series of [(imidazole)nZn-S(H)CH3](2+) and [(imidazole)nZn-SCH3](+) complexes with the CN varied from 1 to 6, n = 0-5. As the number of imidazole ligands coordinated to zinc increases, the S-H proton dissociation energy also increases, (i.e., -S(H)CH3 becomes less acidic), and the Zn-S bond energy decreases. Furthermore, at a constant CN, the S-H proton dissociation energy decreases as the S-Zn-(ImH)n angles increase about their equilibrium position. The zinc-coordinated thiol can become more or less acidic depending upon the position of the coordinated imidazole ligands. The bonding and thermodynamic relationships discussed may apply to larger systems that utilize the [(His)3Zn(II)-L] complex as the catalytic site, including carbonic anhydrase, carboxypeptidase, β-lactamase, the tumor necrosis factor-α-converting enzyme, and the matrix metalloproteinases.

Structures, Hydration, and Electrical Mobilities of Bisulfate Ion-Sulfuric Acid-Ammonia/Dimethylamine Clusters: A Computational Study.

Despite the well-established role of small molecular clusters in the very first steps of atmospheric particle formation, their thermochemical data are still not completely available due to limitation of the experimental techniques to treat such small clusters. We have investigated the structures and the thermochemistry of stepwise hydration of clusters containing one bisulfate ion, sulfuric acid, base (ammonia or dimethylamine), and water molecules using quantum chemical methods. We found that water facilitates proton transfer from sulfuric acid or the bisulfate ion to the base or water molecules, and depending on the hydration level, the sulfate ion was formed in most of the base-containing clusters. The calculated hydration energies indicate that water binds more strongly to ammonia-containing clusters than to dimethylamine-containing and base-free clusters, which results in a wider hydrate distribution for ammonia-containing clusters. The electrical mobilities of all clusters were calculated using a particle dynamics model. The results indicate that the effect of humidity is negligible on the electrical mobilities of molecular clusters formed in the very first steps of atmospheric particle formation. The combination of the results of this study with those previously published on the hydration of neutral clusters by our group provides a comprehensive set of thermochemical data on neutral and negatively charged clusters containing sulfuric acid, ammonia, or dimethylamine.

Effect of ligand protonation on the facilitated ion transfer reactions across oil|water interfaces. V. Applications of forced hydrodynamic conditions

Hydrodynamic forced conditions applied to the aqueous or the organic phase during a potential sweep can be used to elucidate the mechanisms of ion transfer across liquid|liquid interfaces. The aim of this study is to confirm experimentally the previous proposed global mechanisms of facilitated proton transfer via water autoprotolysis and to extend them, controlling the mass transport. We show that proton transfer assisted by quinidine via water autoprotolysis is an interesting example, where the ion transfer reaction occurs with the formation of different products in each phase, i.e., protonated weak base in the organic phase and the hydroxide ion in the aqueous phase. Furthermore, one of the reactants (water) is always in excess with respect to the other one (neutral weak base). These features provide unique characteristics to facilitated proton transfer via water autoprotolysis to be explored by applying forced hydrodynamic conditions.

Redox-induced proton insertion and desertion of zircon-type neodymium chromate(V)

Redox transformation of NdCrVO4 involved by insertion/desertion of protons was examined by XRD, XPS, in situ FT-IR and fuel cell tests. It was found that NdCrO4 caused bulk reduction with H2 gas at around 400°C, changing to amorphous Nd(III)–Cr(III) hydroxide phase. This hydroxide phase, however, could recover to the original zircon type oxide phase by air oxidation at the same temperature region. Proton-conducting ceramic fuel cells having NdCrO4 film as an interlayer between cathode and electrolyte was fabricated and the cell was confirmed to exhibit remarkable power generation giving rise to OCV of more than 1.0V at 500°C. It was speculated that the interlayer facilitates proton transfer from electrolyte to cathode because redox cycling of NdCrO4 and the corresponding hydroxide was driven by the high proton chemical potential at the interface with electrolyte and plenty of oxygen in cathode gases.

Hybrid Bilayer Membrane As a Versatile Electrochemical Platform to Modulate Transport Kinetics of Small Molecules Across a Lipid Monolayer

We report our effort to gate molecular transport through lipids. To probe the kinetics of small molecule delivery in and out of a lipid layer, we monitored the electrochemical response of a redox-active moiety covalently attached to a self-assembled monolayer (SAM) on gold. We prepared the first synthetic dicopper electrocatalyst (CuBTT) on a SAM/Au system for the oxygen reduction reaction (ORR) through rational design based on an aminotriazole derivative discovered previously by our group. The kinetically sluggish ORR proceeds via multiple proton-coupled electron transfer (PCET) steps. By appending a monolayer of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) on top of a CuBTT-SAM to construct a hybrid bilayer membrane (HBM, Figure 1), we suppressed the ORR activity of CuBTT. This inhibition in ORR activity is due to the hydrophobic lipid interior which impedes transmembrane diffusion of the hydrophilic positively-charged protons. In nature, membrane-bound proton carriers deliver protons across lipid bilayers via flip-flop diffusion. Inspired by biological systems, we recovered the ORR activity of CuBTT by incorporating an alkyl phosphate, mono-N-dodecyl phosphate (MDP), in the lipid monolayer of the HBM to facilitate proton transfer to CuBTT. We further discovered that this assisted proton transport behavior can be turned on and off by switching the pH of the bulk solution. This observation allowed us to build a pH-sensitive switch that modulates proton flux to a HBM-embedded ORR electrocatalyst.(1) We believe this HBM platform not only can provide valuable mechanistic insight into PCET reactions, but also lay the foundation for advanced bio-compatible electronics and nanocomputers. The HBM electrochemical platform allows for the precise and independent control of both the thermodynamics and kinetics of proton transfer to a molecular catalyst. We are in the process of understanding the underlying mechanism of the assisted proton transfer process and in search of a quantitative structure-activity relationship between different proton carriers. Apart from studying related HBM platforms with different lipids and proton carriers, embedding redox and pH markers inside a HBM will provide valuable information about the internal environment of the system. We are also interested in controlling the kinetics of other small molecules through the lipid layer, which offers a unique electrochemical platform for drug screening processes.

A mitochondria-targeted protonophoric uncoupler derived from fluorescein.

Linking decyl-triphenyl-phosphonium to fluorescein yields a fluorescent probe that accumulates in energized mitochondria, facilitates proton transfer across membranes and stimulates mitochondrial respiration. This features a mitochondria-targeted uncoupler, being of potential interest for therapeutic use against oxidative stress-related diseases.

Proton-transfer polymerization (HTP): converting methacrylates to polyesters by an N-heterocyclic carbene.

A new polymerization termed proton (H)-transfer polymerization (HTP) has been developed to convert dimethacrylates to unsaturated polyesters. HTP is catalyzed by a selective N-heterocyclic carbene capable of promoting intermolecular Umpolung condensation through proton transfer and proceeds through the step-growth propagation cycles via enamine intermediates. The role of the added suitable phenol, which is critical for achieving an effective HTP, is twofold: shutting down the radically induced chain-growth addition polymerization under HTP conditions (typically at 80-120 °C) and facilitating proton transfer after each monomer enchainment. The resulting unsaturated polyesters have a high thermal stability and can be readily cross-linked to robust polyester materials.

Proton‐Transfer Polymerization (HTP): Converting Methacrylates to Polyesters by an N‐Heterocyclic Carbene

AbstractA new polymerization termed proton (H)‐transfer polymerization (HTP) has been developed to convert dimethacrylates to unsaturated polyesters. HTP is catalyzed by a selective N‐heterocyclic carbene capable of promoting intermolecular Umpolung condensation through proton transfer and proceeds through the step‐growth propagation cycles via enamine intermediates. The role of the added suitable phenol, which is critical for achieving an effective HTP, is twofold: shutting down the radically induced chain‐growth addition polymerization under HTP conditions (typically at 80–120 °C) and facilitating proton transfer after each monomer enchainment. The resulting unsaturated polyesters have a high thermal stability and can be readily cross‐linked to robust polyester materials.

Facilitated proton transfer or protonated species transfer reactions across oil|water interfaces

The main purpose of this paper is to develop the equations for the half-wave potential of facilitated proton transfer or protonated species transfer across liquid|liquid interfaces, including ion pairing. The main equation developed in this research allows simulating different chemical systems (hydrophilic and hydrophobic neutral base, multiple protonated species, ion-pair formation in the organic phase). Five representative chemical systems are studied in detail in order to demonstrate the usefulness of the equations developed. In addition, the effect of the hydrophilicity of neutral weak bases on the domains of predominance of each species is analysed. Finally, the half-wave potential as a function of the pH obtained using the developed equations, are compared to simulated results and to pH-potential diagram.

Role of Two Alternate Water Networks in Compound I Formation in P450eryF

The P450eryF enzyme (CYP107A1) hydroxylates 6-deoxyerythronolide B to erythronolide B during erythromycin synthesis by Saccharopolyspora erythraea. In many P450 enzymes, a conserved "acid-alcohol pair" is believed to participate in the proton shuttling pathway for O2 activation that generates the reactive oxidant (Compound I, Cpd I). In CYP107A1, the alcohol-containing amino acid is replaced with alanine. The crystal structure of DEB bound to CYP107A1 indicates that one of the substrate hydroxyl groups (5-OH) may facilitate proton transfer during O2 activation. We applied molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) techniques to investigate substrate-mediated O2 activation in CYP107A1. In the QM/MM calculations, the QM region was treated by density functional theory, and the MM region was represented by the CHARMM force field. The MD simulations suggest the existence of two water networks around the active site, the one found in the crystal structure involving E360 and an alternative one involving E244. According to the QM/MM calculations, the first proton transfer that converts the peroxo to the hydroperoxo intermediate (Compound 0, Cpd 0) proceeds via the E244 water network with direct involvement of the 5-OH group of the substrate. For the second proton transfer from Cpd 0 to Cpd I, the computed barriers for the rate-limiting homolytic O-O cleavage are similar for the E360 and E244 pathways, and hence both glutamate residues may serve as proton source in this step.

A proton channel allows a hydrogen oxidation catalyst to operate at a moderate overpotential with water acting as a base

We report the incorporation of a simple enzyme-inspired proton channel onto a hydrogen oxidation catalyst. This modification facilitates proton transfer and lowers the overpotential for oxidation of H2 by 300 mV when using water as a base.

Theoretical studies on the mechanism of activation of phosphoprotein phosphatases and purple acid phosphatases suggest an evolutionary strategy to survive in acidic environments

Dephosphorylation reactions of phosphoprotein phosphatases (PPPs) share a common catalytic cycle. In one stage of the cycle, the active site is regenerated through formation of a new nucleophilic μ-hydroxy moiety and reprotonation of the proton donor, His125 (numbered according to the protein phosphatase 1 sequence). To date the exact details of the mechanism of this step remain uncertain. On the basis of recurring observations in several crystal structures, we propose an activation mechanism in which dephosphorylation of PPPs proceeds mainly through proton transfer from the water molecule that bridges the metal ions to His125, which is mediated by another water molecule. Our calculations using hybrid density functional theory and B3LYP functionals support this activation mechanism. We also propose that Asp95 facilitates proton transfer by eliminating the energy barrier and the backbone carbonyl oxygen atom of His248 acts mainly to orient and stabilize the μ-hydroxo (or water molecule) through hydrogen bonding. Furthermore, on the basis of the structural similarities of the active sites of purple acid phosphatases (PAPs) and PPPs, we speculate that PAPs are activated by a dual proton transfer mediated by one water molecule. Our calculations support this hypothesis and indicate that the active site of PAPs can still be active in an acidic environment (in agreement with the acid phosphatase activity of PAPs). Therefore, the variant of the activation mechanism from PPPs to PAPs implies an evolutionary adaptation to acidic environments.

Assessing the Proton Affinities of N,N′-Diamidocarbenes

The gas-phase proton affinities (PAs) of a series of novel diamidocarbenes (DACs) were assessed and compared to various imidazolylidene-based N-heterocyclic carbenes (NHCs) through experimental and computational methods. Apart from a perfluorinated-phenyl derivative (PA = 233 kcal/mol), the calculated and measured PAs for a range of DACs (256-261 kcal/mol) were comparable to those of the NHCs (260-266 kcal/mol). Proton transfer from the protonated carbene to various reference bases, as observed by mass spectrometry, was inhibited by steric bulk and precluded the direct measurement of the PA for the known DACs, N,N'-dimesityl-4,6-diketo-5,5-dimethylpyrimidin-2-ylidene and N,N'-diisopropylphenyl-4,6-diketo-5,5-dimethylpyrimidin-2-ylidene. However, DACs featuring less hindered N-aryl substituents facilitated proton transfer, and the measured PA values were found to be consistent with density functional theory calculations (B3LYP/6-31+G(d)). Notably, the PAs of the DACs studied were similar to those of the NHCs, indicating that the former retain many of the nucleophilic characteristics intrinsic to their parent diaminocarbenes and that the observed differences in chemical reactivity may be primarily attributed to an enhanced electrophilicity.

1.55 Å-resolution structure of ent-copalyl diphosphate synthase and exploration of general acid function by site-directed mutagenesis

BackgroundThe diterpene cyclase ent-copalyl diphosphate synthase (CPS) catalyzes the first committed step in the biosynthesis of gibberellins. The previously reported 2.25Å resolution crystal structure of CPS complexed with (S)-15-aza-14,15-dihydrogeranylgeranyl thiolodiphosphate (1) established the αβγ domain architecture, but ambiguities regarding substrate analog binding remained. MethodUse of crystallization additives yielded CPS crystals diffracting to 1.55Å resolution. Additionally, active site residues that hydrogen bond with D379, either directly or through hydrogen bonded water molecules, were probed by mutagenesis. ResultsThis work clarifies structure–function relationships that were ambiguous in the lower resolution structure. Well-defined positions for the diphosphate group and tertiary ammonium cation of 1, as well as extensive solvent structure, are observed. ConclusionsTwo channels involving hydrogen bonded solvent and protein residues lead to the active site, forming hydrogen bonded “proton wires” that link general acid D379 with bulk solvent. These proton wires may facilitate proton transfer with the general acid during catalysis. Activity measurements made with mutant enzymes indicate that N425, which donates a hydrogen bond directly to D379, and T421, which hydrogen bonds with D379 through an intervening solvent molecule, help orient D379 for catalysis. Residues involved in hydrogen bonds with the proton wire, R340 and D503, are also important. Finally, conserved residue E211, which is located near the diphosphate group of 1, is proposed to be a ligand to Mg2+ required for optimal catalytic activity. General significanceThis work establishes structure–function relationships for class II terpenoid cyclases.