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1.  4-Meth­oxy­benzamidinium hydrogen oxalate monohydrate 
The title hydrated salt, C8H11N2O+·C2HO4 −·H2O, was synthesized by a reaction of 4-meth­oxy­benzamidine (4-amidino­anisole) and oxalic acid in water solution. In the cation, the amidinium group forms a dihedral angle of 15.60 (6)° with the mean plane of the benzene ring. In the crystal, each amidinium unit is bound to three acetate anions and one water mol­ecule by six distinct N—H⋯O hydrogen bonds. The ion pairs of the asymmetric unit are joined by two N—H⋯O hydrogen bonds into ionic dimers in which the carbonyl O atom of the semi-oxalate anion acts as a bifurcated acceptor, thus generating an R 1 2(6) motif. These subunits are then joined through the remaining N—H⋯O hydrogen bonds to adjacent semi-oxalate anions into linear tetra­meric chains running approximately along the b axis. The structure is stabilized by N—H⋯O and O—H⋯O inter­molecular hydrogen bonds. The water mol­ecule plays an important role in the cohesion and the stability of the crystal structure being involved in three hydrogen bonds connecting two semi-oxalate anions as donor and a benzamidinium cation as acceptor.
PMCID: PMC3588951  PMID: 23476187
2.  On the Primary Ionization Mechanism(s) in Matrix-Assisted Laser Desorption Ionization 
A mechanism is proposed for the first step of ionization occurring in matrix-assisted laser desorption ionization, leading to protonated and deprotonated matrix (Ma) molecules ([Ma + H]+ and [Ma − H]− ions). It is based on observation that in solid state, for carboxyl-containing MALDI matrices, the molecules form strong hydrogen bonds and their carboxylic groups can act as both donors and acceptors. This behavior leads to stable dimeric structures. The laser irradiation leads to the cleavage of these hydrogen bonds, and theoretical calculations show that both [Ma + H]+ and [Ma − H]− ions can be formed through a two-photon absorption process. Alternatively, by the absorption of one photon only, a heterodissociation of one of the O–H bonds can lead to a stable structure containing both cationic and anionic sites. This structure could be considered an intermediate that, through the absorption of a further photon, leads to the formation of matrix ions. Some experiments have been performed to evaluate the role of thermal ionization and indicate that its effect is negligible. Some differences have been observed for different matrices in the formation of analyte molecule (M) ion [M + H]+, [M − H]−, M+•, and [M − 2H]-•, and they have been explained in terms of ionization energies, pKa values, and thermodynamic stability.
PMCID: PMC3515899  PMID: 23251835
3.  4-Meth­oxy­benzamidinium nitrate 
The title salt, C8H11N2O+·NO3 −, was synthesized by a reaction between 4-meth­oxy­benzamidine (4-amidino­anisole) and nitric acid. The asymmetric unit comprises a non-planar 4-meth­oxy­benzamidinium cation and a nitrate anion. In the cation, the amidinium group has two similar C—N bond lengths [1.302 (3) and 1.313 (3) Å] and its plane forms a dihedral angle of 32.66 (5)° with the mean plane of the benzene ring. The nitrate–amidinium ion pair is not planar, as the dihedral angle between the planes defined by the CN2 + and NO3 − units is 19.28 (6)°. The ionic components are associated in the crystal via N—H⋯O hydrogen bonds, resulting in a three-dimensional network.
PMCID: PMC3588936  PMID: 23476172
4.  Hybrid Quantum/Classical Molecular Dynamics Simulations of the Proton Transfer Reactions Catalyzed by Ketosteroid Isomerase: Analysis of Hydrogen Bonding, Conformational Motions, and Electrostatics 
Biochemistry  2009;48(44):10608-10619.
Hybrid quantum/classical molecular dynamics simulations of the two proton transfer reactions catalyzed by ketosteroid isomerase are presented. The potential energy surfaces for the proton transfer reactions are described with the empirical valence bond method. Nuclear quantum effects of the transferring hydrogen increase the rates by a factor of ~8, and dynamical barrier recrossings decrease the rates by a factor of 3–4. For both proton transfer reactions, the donor-acceptor distance decreases substantially at the transition state. The carboxylate group of the Asp38 side chain, which serves as the proton acceptor and donor in the first and second steps, respectively, rotates significantly between the two proton transfer reactions. The hydrogen bonding interactions within the active site are consistent with the hydrogen bonding of both Asp99 and Tyr14 to the substrate. The simulations suggest that a hydrogen bond between Asp99 and the substrate is present from the beginning of the first proton transfer step, whereas the hydrogen bond between Tyr14 and the substrate is virtually absent in the first part of this step but forms nearly concurrently with the formation of the transition state. Both hydrogen bonds are present throughout the second proton transfer step until partial dissociation of the product. The hydrogen bond between Tyr14 and Tyr55 is present throughout both proton transfer steps. The active site residues are more mobile during the first step than during the second step. The van der Waals interaction energy between the substrate and the enzyme remains virtually constant along the reaction pathway, but the electrostatic interaction energy is significantly stronger for the dienolate intermediate than for the reactant and product. Mobile loop regions distal to the active site exhibit significant structural rearrangements and, in some cases, qualitative changes in the electrostatic potential during the catalytic reaction. These results suggest that relatively small conformational changes of the enzyme active site and substrate strengthen the hydrogen bonds that stabilize the intermediate, thereby facilitating the proton transfer reactions. Moreover, the conformational and electrostatic changes associated with these reactions are not limited to the active site but rather extend throughout the entire enzyme.
PMCID: PMC2783618  PMID: 19799395
5.  Analysis of Kinetic Isotope Effects for Proton-Coupled Electron Transfer Reactions 
The journal of physical chemistry. A  2009;113(10):2117-2126.
A series of rate constant expressions for nonadiabatic proton-coupled electron transfer (PCET) reactions are analyzed and compared. The approximations underlying each expression are enumerated, and the regimes of validity for each expression are illustrated by calculations on model systems. In addition, the kinetic isotope effects (KIEs) for a series of model PCET reactions are analyzed to elucidate the fundamental physical principles dictating the magnitude of the KIE and the dependence of the KIE on the physical properties of the system, including temperature, reorganization energy, driving force, equilibrium proton donor-acceptor distance, and effective frequency of the proton donor-acceptor mode. These calculations lead to three physical insights that are directly relevant to experimental data. First, these calculations provide an explanation for a decrease in the KIE as the proton donor-acceptor distance increases, even though typically the KIE will increase with increasing equilibrium proton donor-acceptor distance if all other parameters remain fixed. Often the proton donor-acceptor frequency decreases as the proton donor-acceptor distance increases, and these two effects impact the KIE in opposite directions, so either trend could be observed. Second, these calculations provide an explanation for an increase in the KIE as the temperature increases, even though typically the KIE will decrease with increasing temperature if all other parameters remain fixed. The combination of a rigid hydrogen bond, which corresponds to a high proton donor-acceptor frequency, and low solvent polarity, which corresponds to small solvent reorganization energy, allows the KIE to either increase or decrease with temperature, depending on the other properties of the system. Third, these calculations provide insight into the dependence of the rate constant and KIE on the driving force, which has been studied experimentally for a wide range of PCET systems. The rate constant increases as the driving force becomes more negative because excited vibronic product states associated with low free energy barriers and relatively large vibronic couplings become accessible. The ln[KIE] has a maximum near zero driving force and decreases significantly as the driving force becomes more positive or negative because the contributions from excited vibronic states increase as the reaction becomes more asymmetric, and contributions from excited vibronic states decrease the KIE. These calculations and analyses lead to experimentally testable predictions of trends in the KIEs for PCET systems.
PMCID: PMC2880663  PMID: 19182970
6.  Benzamidinium 2-meth­oxy­benzoate 
The title mol­ecular salt, C7H9N2 +.C8H7O3 −, was synthesized by reaction between benzamidine (benzene­carboximidamide) and 2-meth­oxy­benzoic acid. In the cation, the amidinium group has two similar C—N bonds [1.3070 (17) and 1.3145 (16) Å] and is almost coplanar with the benzene ring, making a dihedral angle of 5.34 (12)°. In the anion, the meth­oxy substituent forces the carboxyl­ate group to be twisted by 69.45 (6)° with respect to the plane of the aromatic fragment. In the crystal, the components are connected by two N+—H⋯O− (±)CAHB (charge-assisted hydrogen bonds), forming centrosymmetric ionic dimers with graph-set motif R 2 2(8). These ionic dimers are then joined in ribbons running along the b-axis direction by another R 4 2(8) motif involving the remaining N+—H⋯O− hydrogen bonds. Remarkably, at variance with the well known carb­oxy­lic dimer R 2 2(8) motif, the carboxyl­ate–amidinium pair is not planar, the dihedral angle between the planes defined by the CN2 + and CO2 − atoms being 18.57 (12)°.
PMCID: PMC3770387  PMID: 24046672
7.  Proton-coupled electron transfer in solution, proteins, and electrochemistry 
The journal of physical chemistry. B  2008;112(45):14108-14123.
Recent advances in the theoretical treatment of proton-coupled electron transfer (PCET) reactions are reviewed. These reactions play an important role in a wide range of biological processes, as well as in fuel cells, solar cells, chemical sensors, and electrochemical devices. A unified theoretical framework has been developed to describe both sequential and concerted PCET, as well as hydrogen atom transfer (HAT). A quantitative diagnostic has been proposed to differentiate between HAT and PCET in terms of the degree of electronic nonadiabaticity, where HAT corresponds to electronically adiabatic proton transfer and PCET corresponds to electronically nonadiabatic proton transfer. In both cases, the overall reaction is typically vibronically nonadiabatic. A series of rate constant expressions have been derived in various limits by describing the PCET reactions in terms of nonadiabatic transitions between electron-proton vibronic states. These expressions account for the solvent response to both electron and proton transfer and the effects of the proton donor-acceptor vibrational motion. The solvent and protein environment can be represented by a dielectric continuum or described with explicit molecular dynamics. These theoretical treatments have been applied to numerous PCET reactions in solution and proteins. Expressions for heterogeneous rate constants and current densities for electrochemical PCET have also been derived and applied to model systems.
PMCID: PMC2720037  PMID: 18842015
8.  Concerted Proton-Electron Transfer in the Oxidation of Hydrogen-Bonded Phenols 
Three phenols with pendant, hydrogen-bonded bases (HOAr-B) have been oxidized in MeCN with various one-electron oxidants. The bases are a primary amine (–CPh2NH2), an imidazole, and a pyridine. The product of chemical and quasi-reversible electrochemical oxidations in each case is the phenoxyl radical in which the phenolic proton has transferred to the base, •OAr-BH+, a proton-coupled electron transfer (PCET) process. The redox potentials for these oxidations are lower than other phenols, predominately from the driving force for proton movement. One-electron oxidation of the phenols occurs by a concerted proton-electron transfer (CPET) mechanism, based on thermochemical arguments, isotope effects, and ΔΔG‡/ΔΔG°. The data rule out stepwise paths involving initial electron transfer to form the phenol radical cations [•+HOAr-B] or initial proton transfer to give the zwitterions [−OAr-BH+]. The rate constant for heterogeneous electron transfer from HOAr-NH2 to a platinum electrode has been derived from electrochemical measurements. For oxidations of HOAr-NH2, the dependence of the solution rate constants on driving force, on temperature, and on the nature of the oxidant, and the correspondence between the homogeneous and heterogeneous rate constants, are all consistent with the application of adiabatic Marcus Theory. The CPET reorganization energies, λ = 23 – 56 kcal mol−1, are large in comparison with those for electron transfer reactions of aromatic compounds. The reactions are not highly nonadiabatic, based on minimum values of Hrp derived from the temperature dependence of the rate constants. These are among the first detailed analyses of CPET reactions where the proton and electron move to different sites.
PMCID: PMC2518092  PMID: 16669677
9.  Catalytic Efficiency of Enzymes: A Theoretical Analysis 
Biochemistry  2012;52(12):10.1021/bi301515j.
This brief review analyzes the underlying physical principles of enzyme catalysis, with an emphasis on the role of equilibrium enzyme motions and conformational sampling. The concepts are developed in the context of three representative systems, namely dihydrofolate reductase, ketosteroid isomerase, and soybean lipoxygenase. All of these reactions involve hydrogen transfer, but many of the concepts discussed are more generally applicable. The factors that are analyzed in this review include hydrogen tunneling, proton donor-acceptor motion, hydrogen bonding, pKa shifting, electrostatics, preorganization, reorganization, and conformational motions. The rate constant for the chemical step is determined primarily by the free energy barrier, which is related to the probability of sampling configurations conducive to the chemical reaction. According to this perspective, stochastic thermal motions lead to equilibrium conformational changes in the enzyme and ligands that result in configurations favorable to the breaking and forming of chemical bonds. For proton, hydride, and proton-coupled electron transfer reactions, typically the donor and acceptor become closer to facilitate the transfer. The impact of mutations on the catalytic rate constants can be explained in terms of the factors enumerated above. In particular, distal mutations can alter the conformational motions of the enzyme and therefore the probability of sampling configurations conducive to the chemical reaction. Methods such as vibrational Stark spectroscopy, in which environmentally sensitive probes are introduced site-specifically in the enzyme, provide further insight into these aspects of enzyme catalysis through a combination of experiments and theoretical calculations.
PMCID: PMC3619019  PMID: 23240765
10.  Theoretical Studies of Proton-Coupled Electron Transfer: Models and Concepts Relevant to Bioenergetics 
Coordination chemistry reviews  2008;252(3-4):384-394.
Theoretical studies of proton-coupled electron transfer (PCET) reactions for model systems provide insight into fundamental concepts relevant to bioenergetics. A dynamical theoretical formulation for vibronically nonadiabatic PCET reactions has been developed. This theory enables the calculation of rates and kinetic isotope effects, as well as the pH and temperature dependences, of PCET reactions. Methods for calculating the vibronic couplings for PCET systems have also been developed and implemented. These theoretical approaches have been applied to a wide range of PCET reactions, including tyrosyl radical generation in a tyrosine-bound rhenium polypyridyl complex, phenoxyl/phenol and benzyl/toluene self-exchange reactions, and hydrogen abstraction catalyzed by the enzyme lipoxygenase. These applications have elucidated some of the key underlying physical principles of PCET reactions. The tools and concepts derived from these theoretical studies provide the foundation for future theoretical studies of PCET in more complex bioenergetic systems such as Photosystem II.
PMCID: PMC2971562  PMID: 21057592
proton-coupled electron transfer; proton transfer; electron transfer; hydrogen transfer
11.  Molecular eyes: proteins that transform light into biological information 
Interface Focus  2013;3(5):20130005.
Most biological photoreceptors are protein/cofactor complexes that induce a physiological reaction upon absorption of a photon. Therefore, these proteins represent signal converters that translate light into biological information. Researchers use this property to stimulate and study various biochemical processes conveniently and non-invasively by the application of light, an approach known as optogenetics. Here, we summarize the recent experimental progress on the family of blue light receptors using FAD (BLUF) receptors. Several BLUF photoreceptors modulate second messenger levels and thus represent highly interesting tools for optogenetic application. In order to activate a coupled effector protein, the flavin-binding pocket of the BLUF domain undergoes a subtle rearrangement of the hydrogen network upon blue light absorption. The hydrogen bond switch is facilitated by the ultrafast light-induced proton-coupled electron transfer (PCET) between a tyrosine and the flavin in less than a nanosecond and remains stable on a long enough timescale for biochemical reactions to take place. The cyclic nature of the photoinduced reaction makes BLUF domains powerful model systems to study protein/cofactor interaction, protein-modulated PCET and novel mechanisms of biological signalling. The ultrafast nature of the photoconversion as well as the subtle structural rearrangement requires sophisticated spectroscopic and molecular biological methods to study and understand this highly intriguing signalling process.
PMCID: PMC3915823  PMID: 24511384
photoreceptor; flavin; proton-coupled electron transfer; spectroscopy
12.  Guanidinium 2-(myristoylsulfanyl)ethane­sulfonate 
In the title compound, CH6N3 +·C16H31O4S2 − [systematic name: guanidinium 2-(tetra­deca­noylsulfan­yl)ethane­sulfon­ate], each 2-(myristoyl­thio)­ethane­sulfonate ion displays hydrogen bonding to three guanidinium counter-ions, which themselves display hydrogen bonding to two symmetry-related 2-(myristoylthio)ethanesulfonate ions. Thus each cation forms six N—H⋯O bonds to neighboring anions, thereby self-assembling an extended ladder-type network. The average hydrogen-bond donor–acceptor distance is 2.931 (5) Å. The alkyl chains form the rungs of a ladder with hydrogen-bonding inter­actions forming the side rails.
PMCID: PMC3238917  PMID: 22199766
13.  4-Meth­oxy­benzamidinium bromide 
The title salt, C8H11N2O+·Br−, was synthesized by the reaction between 4-meth­oxy­benzamidine (4-amidino­anisole) and hydro­bromic acid. In the cation, the amidinium group has two similar C—N bonds [1.304 (2) and 1.316 (2) Å], and its plane forms a dihedral angle of 31.08 (5)° with the benzene ring. The ions are associated in the crystal into a three-dimension hydrogen-bonded supra­molecular network featuring N—H+⋯Br− inter­actions.
PMCID: PMC3588269  PMID: 23476438
14.  Kinetic Effects Of Increased Proton Transfer Distance On Proton-Coupled Oxidations Of Phenol-Amines 
Journal of the American Chemical Society  2011;133(43):17341-17352.
To test the effect of varying the proton donor-acceptor distance in proton-coupled electron transfer (PCET) reactions, the oxidation of a bicyclic amino-indanol (2) is compared with that of a closely related phenol with an ortho CPh2NH2 substituent (1). Spectroscopic, structural, thermochemical and computational studies show that the two amino-phenols are very similar, except that the O⋯N distance (dON) is >0.1 Å longer in 2 than in 1. The difference in dON is 0.13 ± 0.03 Å from X-ray crystallography and 0.165 Å from DFT calculations. Oxidations of these phenols by outer-sphere oxidants yield distonic radical cations •OAr–NH3+ by concerted proton-electron transfer (CPET). Simple tunneling and classical kinetic models both predict that the longer donor-acceptor distance in 2 should lead to slower reactions, by ca. two orders of magnitude, as well as larger H/D kinetic isotope effects (KIEs). However, kinetic studies show that the compound with the longer proton-transfer distance, 2, exhibits smaller KIEs and has rate constants that are quite close to those of 1. For example, the oxidation of 2 by the triarylamminium radical cation N(C6H4OMe)3•+ (3a+) occurs at (1.4 ± 0.1) × 104 M-1 s-1, only a factor of two slower than the closely related reaction of 1 with N(C6H4OMe)2(C6H4Br)•+ (3b+). This difference in rate constants is well accounted for by the slightly different free energies of reaction: ΔG°(2 + 3a+) = +0.078 V vs. ΔG°(1 + 3b+) = +0.04 V. The two phenol-amines do display some subtle kinetic differences: for instance, compound 2 has a shallower dependence of CPET rate constants on driving force (Brønsted α, Δln(k)/Δln(Keq)). These results show that the simple tunneling model is not a good predictor of the effect of proton donor-acceptor distance on concerted-electron transfer reactions involving strongly hydrogen-bonded systems. Computational analysis of the observed similarity of the two phenols emphasizes the importance of the highly anharmonic O⋯H⋯N potential energy surface and the influence of proton vibrational excited states.
PMCID: PMC3228417  PMID: 21919508
15.  2-Amino-5-methyl­pyridinium 2-amino­benzoate 
In the 2-amino­benzoate anion of the title salt, C6H9N2 +·C7H6NO2 −, an intra­molecular N—H⋯O hydrogen bond is observed. The dihedral angle between the ring and the CO2 group is 8.41 (13)°. In the crystal, the protonated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl­ate O atoms via a pair of N—H⋯O hydrogen bonds, forming an R 2 2(8) ring motif. The ion pairs are further connected via N—H⋯O hydrogen bonds, resulting in a donor–donor–acceptor–acceptor (DDAA) array of quadruple hydrogen bonds. The crystal structure also features a weak N—H⋯O hydrogen bond and a C—H⋯π inter­action, resulting in a three-dimensional network.
PMCID: PMC3515287  PMID: 23284507
16.  Theory of Proton-Coupled Electron Transfer in Energy Conversion Processes 
Accounts of chemical research  2009;42(12):1881-1889.
Proton-coupled electron transfer (PCET) reactions play an essential role in a broad range of energy conversion processes, including photosynthesis and respiration. These reactions also form the basis of many types of solar fuel cells and electrochemical devices. Recent advances in the theory of PCET enable the prediction of the impact of system properties on the reaction rates. These predictions may guide the design of more efficient catalysts for energy production, including those based on artificial photosynthesis and solar energy conversion. This Account summarizes the theoretically predicted dependence of PCET rates on system properties and illustrates potential approaches for tuning the reaction rates in chemical systems.
A general theoretical formulation for PCET reactions has been developed over the past decade. In this theory, PCET reactions are described in terms of nonadiabatic transitions between the reactant and product electron-proton vibronic states. A series of nonadiabatic rate constant expressions for both homogeneous and electrochemical PCET reactions have been derived in various well-defined limits. Recently this theory has been extended to include the effects of solvent dynamics and to describe ultrafast interfacial PCET. Analysis of the rate constant expressions provides insight into the underlying physical principles of PCET and enables the prediction of the dependence of the rates on the physical properties of the system. Moreover, the kinetic isotope effect, which is the ratio of the rates for hydrogen and deuterium, provides a useful mechanistic probe. Typically the PCET rate will increase as the electronic coupling and temperature increase and as the total reorganization energy and equilibrium proton donor-acceptor distance decrease. The rate constant is predicted to increase as the driving force becomes more negative, rather than exhibit turnover behavior in the inverted region, because excited vibronic product states associated with low free energy barriers and relatively large vibronic couplings become accessible. The physical basis for the experimentally observed pH dependence of PCET reactions has been debated in the literature. When the proton acceptor is a buffer species, the pH dependence may arise from the protonation equilibrium of the buffer. It could also arise from kinetic complexity of competing concerted and sequential PCET reaction pathways. In electrochemical PCET, the heterogeneous rate constants and current densities depend strongly on the overpotential. The change in equilibrium proton donor-acceptor distance upon electron transfer may lead to asymmetries in the Tafel plots and deviations of the transfer coefficient from the standard value of one-half at zero overpotential.
Applications of this theory to experimentally studied systems illustrate approaches that can be utilized to tune the PCET rate. For example, the rate can be tuned by changing the pH or using different buffer species as proton acceptors. The rate can also be tuned with site-specific mutagenesis in biological systems or chemical modifications that vary the substituents on the redox species in chemical systems. Understanding the impact of these changes on the PCET rate may assist experimental efforts to enhance energy conversion processes.
PMCID: PMC2841513  PMID: 19807148
17.  Intramolecular “Hydroiminiumation and –amidiniumation” of Alkenes: A Convenient, Flexible, and Scalable Route to Cyclic Iminium and Imidazolinium Salts 
The Journal of organic chemistry  2007;72(9):3492-3499.
Addition of a stoichiometric amount of HCl to alkenylaldimines, -formamidines, and -amidines results in the protonation of the sp2-nitrogen atom. The resulting alkenylaldiminium, -formamidinium, and -amidinium salts can be isolated and fully characterized, including single-crystal X-ray diffraction studies. Heating solutions of these salts induces ring closure cleanly and regioselectively via formal “exo” addition of the nitrogen–hydrogen bond to the pendent carbon–carbon double bond, affording the corresponding cyclic aldiminium, dihydroisoquinolinium, and imidazolinium salts. Of special interest, novel 4,4-disubstituted imidazolinium salts are accessible via this synthetic route. Similarly, addition of phosgene to alkenyl ureas and alkenyl amides, followed by gentle heating, cleanly affords C-chloro imidazolinium, and cyclic C-chloro iminium salts, respectively. Treatment of the latter with tetrakis(triphenylphosphine)-palladium allows for the preparation of the first transition-metal complex bearing a cyclic arylaminocarbene as ligand. Deuterium labeling experiments suggest that the mechanism of the hydroiminiumation and -amidiniumation reactions involves an intramolecular proton transfer to the double bond in the rate-determining step. This novel synthetic methodology gives access to a variety of N-heterocyclic carbene (NHC) and cyclic alkyl- and arylaminocarbene (CAAC) precursors.
PMCID: PMC2440693  PMID: 17408289
18.  Biological effects of deuteronation: ATP synthase as an example 
In nature, deuterium/hydrogen ratio is ~1/6600, therefore one of ~3300 water (H2O) molecules is deuterated (HOD + D2O). In body fluids the ratio of deuterons to protons is ~1/15000 because of the lower ionization constant of heavy water. The probability of deuteronation rather than protonation of Asp 61 on the subunit c of F0 part of ATP synthase is also ~1/15000. The contribution of deuteronation to the pKa of Asp 61 is 0.35.
Theory and Discussion
In mitochondria, the release of a deuteron into the matrix side half-channel of F0 is likely to be slower than that of a proton. As another example, deuteronation may slow down electron transfer in the electron transport chain (ETC) by interfering with proton coupled electron transport reactions (PCET), and increase free radical production through the leakage of temporarily accumulated electrons at the downstream complexes.
Deuteronation, as exemplified by ATP synthase and the ETC, may interfere with the conformations and functions of many macromolecules and contribute to some pathologies like heavy water toxicity and aging.
PMCID: PMC1808445  PMID: 17316427
19.  Branched Activation- and Catalysis-Specific Pathways for Electron Relay to the Manganese/Iron Cofactor in Ribonucleotide Reductase from Chlamydia trachomatis† 
Biochemistry  2008;47(33):8477-8484.
A conventional class I (subclass a or b) ribonucleotide reductase (RNR) employs a tyrosyl radical (Y•) in its R2 subunit for reversible generation of a 3′-hydrogen-abstracting cysteine radical in its R1 subunit by proton-coupled electron transfer (PCET) through a network of aromatic amino acids spanning the two subunits. The class Ic RNR from the human pathogen Chlamydia trachomatis (Ct) uses a MnIV/FeIII cofactor (specifically, the MnIV ion) in place of the Y• for radical initiation. Ct R2 is activated when its MnII/FeII form reacts with O2 to generate a MnIV/FeIV intermediate, which decays by reduction of the FeIV site to the active MnIV/FeIII state. Here we show that the reduction step in this sequence is mediated by residue Y222. Substitution of Y222 with F retards the intrinsic decay of the MnIV/FeIV intermediate by ∼10-fold and diminishes the ability of ascorbate to accelerate the decay by ∼65-fold but has no detectable effect on the catalytic activity of the MnIV/FeIII–R2 product. By contrast, substitution of Y338, the cognate of the subunit interfacial R2 residue in the R1 ⇔ R2 PCET pathway of the conventional class I RNRs [Y356 in Escherichia coli (Ec) R2], has almost no effect on decay of the MnIV/FeIV intermediate but abolishes catalytic activity. Substitution of W51, the Ct R2 cognate of the cofactor-proximal R1 ⇔ R2 PCET pathway residue in the conventional class I RNRs (W48 in Ec R2), both retards reduction of the MnIV/FeIV intermediate and abolishes catalytic activity. These observations imply that Ct R2 has evolved branched pathways for electron relay to the cofactor during activation and catalysis. Other R2s predicted also to employ the Mn/Fe cofactor have Y or W (also competent for electron relay) aligning with Y222 of Ct R2. By contrast, many R2s known or expected to use the conventional Y•-based system have redox-inactive L or F residues at this position. Thus, the presence of branched activation- and catalysis-specific electron relay pathways may be functionally important uniquely in the Mn/Fe-dependent class Ic R2s.
PMCID: PMC2681183  PMID: 18656954
20.  Poly[(μ2-nitrato-κ2 O:O′)(μ2-pyrimidin­ium-2-carboxyl­ato-κ2 O:O′)lithium(I)] 
In the structure of the title compound, [Li(C5H4N2O2)(NO3)]n, the LiI ion is coordinated by two carboxyl­ate O atoms donated by two ligands and two nitrate O atoms in a distorted tetrahedral geometry. LiI ions, bridged by carboxyl­ate O atoms, form mol­ecular ribbons composed of dimeric units. Two nitrate O atoms link the ribbons into mol­ecular layers parallel to (001). Hydrogen bonds are active between protonated heterocyclic N atoms as donors and carboxyl­ate O atoms as acceptors. The layers are held together by van der Waals inter­actions.
PMCID: PMC3120533  PMID: 21754689
21.  R22(8) motifs in Aminopyrimidine sulfonate/carboxylate interactions: Crystal structures of pyrimethaminium benzenesulfonate monohydrate (2:2:1) and 2-amino-4,6-dimethylpyrimidinium sulfosalicylate dihydrate (4:2:2) 
Pyrimethamine [2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine] is an antifolate drug used in anti-malarial chemotherapy. Pyrimidine and aminopyrimidine derivatives are biologically important compounds owing to their natural occurrence as components of nucleic acids.
In the crystal structures of two organic salts, namely pyrimethaminium benzenesulfonate monohydrate 1 and 2-amino-4, 6-dimethylpyrimidinium 3-carboxy-4-hydroxy benzenesulfonate dihydrate 2, pyrimethamine (PMN) and 2-amino-4,6-dimethylpyrimidine (AMPY) are protonated at one of the nitrogens in the pyrimidine rings. In both the PMN and AMPY sulfonate complexes, the protonated pyrimidine rings are hydrogen bonded to the sulfonate groups, forming a hydrogen-bonded bimolecular ring motif with graph-set notation R22(8). The sulfonate group mimics the carboxylate anion's mode of association, which is more commonly seen when binding with 2-aminopyrimidines. In compound 1, the PMN moieties are centrosymmetrically paired through a complementary DADA array of hydrogen bonds. In compound 2, two types of bimolecular cyclic hydrogen bonded R22(8) motifs (one involving the carboxylate group and the other involving sulfonate group) coexist. Furthermore, this compound is stabilized by intra and intermolecular O-H...O hydrogen bonds.
The crystal structures of pyrimethaminium benzenesulfonate monohydrate and 2-amino-4,6-dimethylpyrimidinium sulfosalicylate dihydrate have been investigated in detail. In compound 1, the R22(8) motif involving the sulfonate group is present. The role the sulfonic acid group plays in mimicking the carboxylate anions is thus evident. In compound 2, two types of bimolecular cyclic hydrogen bonded R22(8) motifs (one involving the carboxylate group and the other involving sulfonate group) coexist. In both the compounds base pairing also occurs. Thus homo and hetero synthons are present.
PMCID: PMC2238812  PMID: 17999751
22.  2-Amino-5-chloro­pyridinium salicylate 
In the crystal structure of the title salt, C5H6ClN2 +·C7H5O3 −, the protonated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl­ate O atoms via a pair of N—H⋯O hydrogen bonds, forming R 2 2(8) ring motifs. These motifs are centrosymmetrically paired via N—H⋯O hydrogen bonds, forming a complementary donor–donor–acceptor–acceptor (DDAA) array. A typical intra­molecular O—H⋯O hydrogen bond is also observed in the salicylate anion. The crystal structure is further stabilized by weak C—H⋯π inter­actions.
PMCID: PMC2979380  PMID: 21579496
23.  Proton-coupled electron transfer: the mechanistic underpinning for radical transport and catalysis in biology 
Charge transport and catalysis in enzymes often rely on amino acid radicals as intermediates. The generation and transport of these radicals are synonymous with proton-coupled electron transfer (PCET), which intrinsically is a quantum mechanical effect as both the electron and proton tunnel. The caveat to PCET is that proton transfer (PT) is fundamentally limited to short distances relative to electron transfer (ET). This predicament is resolved in biology by the evolution of enzymes to control PT and ET coordinates on highly different length scales. In doing so, the enzyme imparts exquisite thermodynamic and kinetic controls over radical transport and radical-based catalysis at cofactor active sites. This discussion will present model systems containing orthogonal ET and PT pathways, thereby allowing the proton and electron tunnelling events to be disentangled. Against this mechanistic backdrop, PCET catalysis of oxygen–oxygen bond activation by mono-oxygenases is captured at biomimetic porphyrin redox platforms. The discussion concludes with the case study of radical-based quantum catalysis in a natural biological enzyme, class I Escherichia coli ribonucleotide reductase. Studies are presented that show the enzyme utilizes both collinear and orthogonal PCET to transport charge from an assembled diiron-tyrosyl radical cofactor to the active site over 35 Å away via an amino acid radical-hopping pathway spanning two protein subunits.
PMCID: PMC1647304  PMID: 16873123
proton-coupled electron transfer; amino acid radicals; tunnelling; tyrosine; catalysis; ribonucleotide reductase
24.  Proton coupled electron transfer and redox active tyrosines in Photosystem II 
In this article, progress in understanding proton coupled electron transfer (PCET) in photosystem II is reviewed. Changes in acidity/basicity may accompany oxidation/reduction reactions in biological catalysis. Alterations in the proton transfer pathway can then be used to alter the rates of the electron transfer reactions. Studies of the bioenergetic complexes have played a central role in advancing our understanding of PCET. Because oxidation of the tyrosine results in deprotonation of the phenolic oxygen, redox active tyrosines are involved in PCET reactions in several enzymes. This review focuses on PCET involving the redox active tyrosines in photosystem II. Photosystem II catalyzes the light-driven oxidation of water and reduction of plastoquinone. Photosystem II provides a paradigm for the study of redox active tyrosines, because this photosynthetic reaction center contains two tyrosines with different roles in catalysis. The tyrosines, YZ and YD, exhibit differences in kinetics and midpoint potentials, and these differences must be due to noncovalent interactions with the protein environment. Here, studies of YD and YZ and relevant model compounds are described.
PMCID: PMC3164834  PMID: 21419640
oxygen evolution; EPR spectroscopy; manganese cluster; midpoint potential; water oxidation
25.  catena-Poly[[(diaqua­zinc)-μ-3-carb­oxy­pyrazine-2-carboxyl­ato-κ4 N 1,O 2;N 4,O 3] nitrate] 
The crystal structure of the title compound, {[Zn(C6H3N2O4)(H2O)2]NO3}n, is built of zigzag cationic chains propagating in [010] with nitrate anions located in the space between the chains. The ZnII ion is coordinated by N and O atoms of two symmetry-related ligands in equatorial sites, and by two water O atoms at the axial sites of a distorted octa­hedron. One carboxyl­ate group of the ligand remains protonated, serving as a donor in a short intra­molecular O—H⋯O hydrogen bond. The coordinated water mol­ecules are donors and the nitrate O atoms act as acceptors in a network of O—H⋯O hydrogen bonds.
PMCID: PMC3254337  PMID: 22259370

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