Hydrogen-Bond Free Energy of Local Biological Water

Here, we propose an experimental methodology based on femtosecond-resolved fluorescence spectroscopy to measure the hydrogen (H)-bond free energy of water at protein surfaces under isothermal conditions. A demonstration was conducted by installing a non-canonical isostere of tryptophan (7-azatryptophan) at the surface of a coiled-coil protein to exploit the photoinduced proton transfer of its chromophoric moiety, 7-azaindole. The H-bond free energy of this biological water was evaluated by comparing the rates of proton transfer, sensitive to the hydration environment, at the protein surface and in bulk water, and it was found to be higher than that of bulk water by 0.4 kcal mol⁻¹. The free-energy difference is dominated by the entropic cost in the H-bond network among water molecules at the hydrophilic and charged protein surface. Our study opens a door to accessing the energetics and dynamics of local biological water to give insight into its roles in protein structure and function.     

How Does a Membrane Protein Achieve a Vectorial Proton Transfer Via Water Molecules?

We present a detailed mechanism for the proton transfer from a protein‐bound protonated water cluster to the bulk water directed by protein side chains in the membrane protein bacteriorhodopsin. We use a combined approach of time‐resolved Fourier transform infrared spectroscopy, molecular dynamics simulations, and X‐ray structure analysis to elucidate the functional role of a hydrogen bond between Ser193 and Glu204. These two residues seal the internal protonated water cluster from the bulk water and the protein surface. During the photocycle of bacteriorhodopsin, a transient protonation of Glu204 leads to a breaking of this hydrogen bond. This breaking opens the gate to the extracellular bulk water, leading to a subsequent proton release from the protonated water cluster. We show in detail how the protein achieves vectorial proton transfer via protonated water clusters in contrast to random proton transfer in liquid water.     

A Theoretical Investigation on N7(H)→N9(H)Tautomerization of Isolated and Monohydrated 2,6-Dithiopurine Combined with IPCM Solvent Model

The tautomerization reaction mechanism has been reported between N7(H) and N9(H) of isolated and monohydrated 2,6‐dithiopurine using B3LYP/6‐311+G(d,p). The isodensity polarized continuum model (IPCM) in the self‐consistent reaction field (SCRF) method is employed to account for the solvent effect of water on the tautomerization reaction activation energies. The results show that the two pathways P(1) (via the carbene intermediate I1) and P(2) (via the sp³‐hybrid intermediate I2) are found in intramolecular proton transfer, and each pathway is composed by two primary steps. The calculated activation energy barriers of the rate‐determining steps in isolated 2,6‐dithiopurine N7(H)→N9(H) tautomerism are 308.2 and 220.0 kJ·mol^?1 in the two pathways, respectively. Interestingly, in one‐water molecule catalyst, it dramatically lowers the N7(H)→N9(H) energy barriers by the concerted double proton transfer mechanism in P(1), favoring the formation of 2,6‐dithiopurine N9(H). However, the single proton transfer mechanism assisted with out‐of‐plane water in the first step of P(2) increases the activation energy barrier from 220.0 to 232.3 kJ·mol^?1, while the second step is the out‐of‐plane concerted double proton transfer mechanism, indicating that they will be less preferable for proton transfer. Additionally, the results also show that all the pathways are put into the aqueous solution, and the activation energy barriers have no significant changes. Therefore, the long‐range electrostatic effect of bulk solvent has no significant impact on proton transfer reactions and the interaction with explicit water molecules will significantly influence proton transfer reactions.     

A comparative study of open‐close and related rotamers methods to evaluate the intramolecular hydrogen bond energies in 3‐imino‐propen‐1‐ol and its derivatives

MP2 study of O? H…N intramolecular hydrogen bond (IMHB) in 3‐imino‐propen‐1‐ol and its derivatives were performed and their IMHB energies were obtained using the related rotamers and open‐close methods. Also the topological properties of electron density distribution and charge transfer energy associated with IMHB were gained by quantum theory of atoms in molecules and natural bond orbital theory, respectively. The computational results reveal that the related rotamers method energies are well correlates with geometrical parameters, topological parameters at hydrogen bond and ring critical points, integrated properties, proton transfer barrier and charge transfer energy of O? H…N unit. Surprisingly, it was found that the open‐close hydrogen bond energies cannot represent good linear correlations with these parameters. Consequently, we extrapolate a number of equations that can be used in estimation of O? H…N IMHB energy in complex biological systems. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012     

Water-wire catalysis in photoinduced acid-base reactions

The pronounced ability of water to form a hyperdense hydrogen (H)-bond network among itself is at the heart of its exceptional properties. Due to the unique H-bonding capability and amphoteric nature, water is not only a passive medium, but also behaves as an active participant in many chemical and biological reactions. Here, we reveal the catalytic role of a short water wire, composed of two (or three) water molecules, in model aqueous acid-base reactions synthesizing 7-hydroxyquinoline derivatives. Utilizing femtosecond-resolved fluorescence spectroscopy, we tracked the trajectories of excited-state proton transfer and discovered that proton hopping along the water wire accomplishes the reaction more efficiently compared to the transfer occurring with bulk water clusters. Our finding suggests that the directionality of the proton movements along the charge-gradient H-bond network may be a key element for long-distance proton translocation in biological systems, as the H-bond networks wiring acidic and basic sites distal to each other can provide a shortcut for a proton in searching a global minimum on a complex energy landscape to its destination.     

Solvent effects on glycine II. Water-assisted tautomerization

The water-assisted tautomerization of glycine has been investigated at the B3LYP/6-31+G** level using supermolecules containing up to six water molecules as well as considering a 1:1 glycine-water complex embedded in a continuum. The conformations of the tautomers in this mechanism do not display an intramolecular H bond, instead the functional groups are bridged by a water molecule. The replacement of the intramolecular H bond by the bridging water reduces the polarity of the N-H bond in the zwitterion and increases that of the O-H bond in the neutral, stabilizing the zwitterion. Both the charge transfer effects and electrostatic interactions stabilize the nonintramolecularly H-bonded zwitterion conformer over the intramolecularly hydrogen bonded one. The nonintramolecularly H-bonded neutral is favored only by charge transfer effects. Although there is no strong evidence whether the intramolecularly hydrogen bonded or non hydrogen bonded structures are favored in the bulk solution represented as a dielectric continuum, it is likely that the latter species are more stable. The free energy of activation of the water-assisted mechanism is higher than the intramolecular proton transfer channel. However, when the presumably higher conformational energy of the zwitterion reacting in the intramolecular mechanism is taken into account, both mechanisms are observed to compete. The various conformers of the neutral glycine may form via multiple proton transfer reactions through several water molecules instead of a conformational rearrangement.     

Periodicity in proton conduction along a H‐bonded chain. Application to biomolecules

Molecular complexes are constructed to simulate proton transfer channels of the influenza A virus and of the active site of carbonic anhydrase. These complexes consist of proton donor and acceptor groups connected by a chain of water molecules. Quantum chemical calculations on the methylimidazole(H⁺)? H₂O? CH₃COO^? model of the M2 virus channel indicate free translational motion of the water molecule between donor and acceptor, as well as concerted transfer of both H‐bond protons. The proton transfer barrier does not depend on the position of the bridged water molecule and varies linearly with the difference of electrostatic potentials between the donor and acceptor. When the water chain is elongated, and with various donor and acceptor models, periodicity appears in the H‐bond lengths and the progression of proton transfer in each link. This “wave” is shown to propagate along the chain, as it is driven by the displacement of a single proton. One can thereby estimate the velocity of the proton wave and proton conduction time. Computations are performed to examine the influence of immersing the system within a polarizable medium. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

Computer simulation of the chemical catalysis of DNA polymerases: discriminating between alternative nucleotide insertion mechanisms for T7 DNA polymerase

Understanding the chemical step in the catalytic reaction of DNA polymerases is essential for elucidating the molecular basis of the fidelity of DNA replication. The present work evaluates the free energy surface for the nucleotide transfer reaction of T7 polymerase by free energy perturbation/empirical valence bond (FEP/EVB) calculations. A key aspect of the enzyme simulation is a comparison of enzymatic free energy profiles with the corresponding reference reactions in water using the same computational methodology, thereby enabling a quantitative estimate for the free energy of the nucleotide insertion reaction. The reaction is driven by the FEP/EVB methodology between valence bond structures representing the reactant, pentacovalent intermediate, and the product states. This pathway corresponds to three microscopic chemical steps, deprotonation of the attacking group, a nucleophilic attack on the P(alpha) atom of the dNTP substrate, and departure of the leaving group. Three different mechanisms for the first microscopic step, the generation of the RO(-) nucleophile from the 3'-OH hydroxyl of the primer, are examined: (i) proton transfer to the bulk solvent, (ii) proton transfer to one of the ionic oxygens of the P(alpha) phosphate group, and (iii) proton transfer to the ionized Asp654 residue. The most favorable reaction mechanism in T7 pol is predicted to involve the proton transfer to Asp654. This finding sheds light on the long standing issue of the actual role of conserved aspartates. The structural preorganization that helps to catalyze the reaction is also considered and analyzed. The overall calculated mechanism consists of three subsequent steps with a similar activation free energy of about 12 kcal/mol. The similarity of the activation barriers of the three microscopic chemical steps indicates that the T7 polymerase may select against the incorrect dNTP substrate by raising any of these barriers. The relative height of these barriers comparing right and wrong dNTP substrates should therefore be a primary focus of future computational studies of the fidelity of DNA polymerases.     

A Mechanistic Study of the Spontaneous Hydrolysis of Glycylserine as the Simplest Model for Protein Self‐Cleavage

A common feature of several classes of intrinsically reactive proteins with diverse biological functions is that they undergo self‐catalyzed reactions initiated by an N→O or N→S acyl shift of a peptide bond adjacent to a serine, threonine, or cysteine residue. In this study, we examine the N→O acyl shift initiated peptide‐bond hydrolysis at the serine residue on a model compound, glycylserine (GlySer), by means of DFT and ab initio methods. In the most favorable rate‐determining transition state, the serine ?COO^? group acts as a general base to accept a proton from the attacking ?OH function, which results in oxyoxazolidine ring closure. The calculated activation energy (29.4 kcal mol^?1) is in excellent agreement with the experimental value, 29.4 kcal mol^?1, determined by ¹H NMR measurements. A reaction mechanism for the entire process of GlySer dipeptide hydrolysis is also proposed. In the case of proteins, we found that when no other groups that may act as a general base are available, the N→O acyl shift mechanism might instead involve a water‐assisted proton transfer from the attacking serine ?OH group to the amide oxygen. However, the calculated energy barrier for this process is relatively high (33.6 kcal mol^?1), thus indicating that in absence of catalytic factors the peptide bond adjacent to serine is no longer a weak point in the protein backbone. An analogous rearrangement involving the amide N‐protonated form, rather than the principle zwitterion form of GlySer, was also considered as a model for the previously proposed mechanism of sea‐urchin sperm protein, enterokinase, and agrin (SEA) domain autoproteolysis. The calculated activation energy (14.3 kcal mol^?1) is significantly lower than the experimental value reported for SEA (≈21 kcal mol^?1), but is still in better agreement as compared to earlier theoretical attempts.     

Proton transfer and associated molecular rearrangements in the photocycle of photoactive yellow protein: role of water molecular migration on the proton transfer reaction

The mechanism of the proton transfer and the concomitant molecular structural and hydrogen bond rearrangements after the photoisomerization of the chromophore in the photocycle of photoactive yellow protein are theoretically investigated by using the QM/MM method and molecular dynamics calculations. The free energy surface along this proton-transfer process is determined. This work suggests the important role of the water molecular migration into the moiety of chromophore, which facilitates proton transfer by the hydrogen bond rearrangement and the hydration of the pB' state.     

The Equally Important Role of Adenine Derivatives to That of Pyrimidine Derivatives in Near‐0 eV Electron‐Induced DNA Lesions

The role of adenine (A) derivatives in DNA damage is scarcely studied due to the low electron affinity of base A. Experimental studies demonstrate that low‐energy electron (LEE) attachment to adenine derivatives complexed with amino acids induces barrier‐free proton transfer producing the neutral N₇‐hydrogenated adenine radicals rather than conventional anionic species. To explore possible DNA lesions at the A sites under physiological conditions, probable bond ruptures in two models—N₇‐hydrogenated 2′‐deoxyadenosine‐3′‐monophosphate (3′‐dA(N7H)MPH) and 2′‐deoxyadenosine‐5′‐monophosphate (5′‐dA(N7H)MPH), without and with LEE attachment—are studied by DFT. In the neutral cases, DNA backbone breakage and base release resulting from C_3′?O_3′ and N₉?C_1′ bond ruptures, respectively, by an intramolecular hydrogen‐transfer mechanism are impossible due to the ultrahigh activation energies. On LEE attachment, the respective C_3′?O_3′ and N₉?C_1′ bond ruptures in [3′‐dA(N7H)MPH]^? and [5′‐dA(N7H)MPH]^? anions via a pathway of intramolecular proton transfer (PT) from the C_2′ site of 2′‐deoxyribose to the C₈ atom of the base moiety become effective, and this indicates that substantial DNA backbone breaks and base release can occur at non‐3′‐end A sites and the 3′‐end A site of a single‐stranded DNA in the physiological environment, respectively. In particular, compared to the results of previous theoretical studies, not only are the electron affinities of 3′‐dA(N7H)MPH and 5′‐dA(N7H)MPH comparable to those of hydrogenated pyrimidine derivatives, but also the lowest energy requirements for the C_3′?O_3′ and N₉‐glycosidic bond ruptures in [3′‐dA(N7H)MPH]^? and [5′‐dA(N7H)MPH]^? anions, respectively, are comparable to those for the C_3′?O_3′ and N₁‐glycosidic bond cleavages in corresponding anionic hydrogenated pyrimidine derivatives. Thus, it can be concluded that the role of adenine derivatives in single‐stranded DNA damage is equally important to that of pyrimidine derivatives in an irradiated cellular environment.     

Quantum chemical study of the hydrogen‐bonded patterns in A · T base pair of DNA: Origins of tautomeric mispairs,base flipping,and Watson–Crick ⇒ Hoogsteen conversion

The current work aims to thoroughly investigate a variety of facets of the hydrogen‐bond pattern of the Watson–Crick A · T base pair of DNA. It offers a novel mechanism of the origin of the hydrogen‐bonded mispairing in the A · T base pair based on the analysis of the lower‐energy portion of the total potential energy surface of all possible rearrangements of the hydrogen‐bond patterns in this pair, performed at the Hartree–Fock (HF), second‐order Moller–Plesset (MP2)//HF, and B3LYP computational levels in conjunction with 6‐31+G(d) basis set. The specific novelty of this mechanism is that the primary step consists of a single proton transfer along the N₃(T)–H … N₁ (A) hydrogen bond, thus leading to a transition state that is not directly related to the proton transfer. Rather, it governs the interbase shift within the A · T pair switching the hydrogen‐bonded pattern and then separating the normal A · T pair from the mispairing valley on its potential energy surface. The latter comprises three mismatched base pairs, easily converted to each other because of lower barriers (≈1 kcal/mol) of the corresponding proton transfers. It is demonstrated that, in terms of the Gibbs free energy taken at room T = 298.15 K, the most stable mispair in such valley is predicted to be less stable by 9.7 ± 2 kcal/mol than the Watson–Crick pair, thus implying that the spontaneous point mutations of this type occur as infrequently as to be characterized by an equilibrium constant of 10^?6 to 10^?9. This estimate falls into the well‐known experimental range of mutation frequency per base pair. The structure of a so‐called “base flipping” of the A · T base pair, originated from a breaking of its N₃(T)‐H … N₁ (A) hydrogen bond, is also found and reported in the current work for the first time. The transition state A · T ${}_{\text{ts}}^{\text{WC?H}}$ , which governs the conversion of the Watson–Crick pair of adenine · thymine into the Hoogsteen one and is related to a breaking of the N₆(A)–H … O₄(T), is also obtained and its energetical and geometrical features are discussed. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2003     

Transport Processes at α‐Quartz–Water Interfaces: Insights from First‐Principles Molecular Dynamics Simulations

Car–Parrinello molecular dynamics (CP–MD) simulations are performed at high temperature and pressure to investigate chemical interactions and transport processes at the α‐quartz–water interface. The model system initially consists of a periodically repeated quartz slab with O‐terminated and Si‐terminated (1000) surfaces sandwiching a film of liquid water. At a temperature of 1000 K and a pressure of 0.3 GPa, dissociation of H₂O molecules into H⁺ and OH^? is observed at the Si‐terminated surface. The OH^? fragments immediately bind chemically to the Si‐terminated surface while Grotthus‐type proton diffusion through the water film leads to protonation of the O‐terminated surface. Eventually, both surfaces are fully hydroxylated and no further chemical reactions are observed. Due to the confinement between the two hydroxylated quartz surfaces, water diffusion is reduced by about one third in comparison to bulk water. Diffusion properties of dissolved SiO₂ present as Si(OH)₄ in the water film are also studied. We do not observe strong interactions between the hydroxylated quartz surfaces and the Si(OH)₄ molecule as would have been indicated by a substantial lowering of the Si(OH)₄ diffusion coefficient along the surface. No spontaneous dissolution of quartz is observed. To study the mechanism of dissolution, constrained CP–MD simulations are done. The associated free energy profile is calculated by thermodynamic integration along the reaction coordinate. Dissolution is a stepwise process in which two Si? O bonds are successively broken. Each bond breaking between a silicon atom at the surface and an oxygen atom belonging to the quartz lattice is accompanied by the formation of a new Si? O bond between the silicon atom and a water molecule. The latter loses a proton in the process which eventually leads to protonation of the oxygen atom in the cleaved quartz Si? O bond. The final solute species is Si(OH)₄.     

Computational study of structures and proton transfer in hydrogen‐bonded ammonia complexes using semiempirical valence‐bond approach

In this study, the seGVB method was implemented for the N H bonding system, specifically for hydrogen‐bonded ammonia complexes, and the model well reproduces the MP2 geometries and energetics. A comparison between the ammonia dimer and water dimer is given from the viewpoint of valance‐bond structures in terms of the calculated bond energies and pair–pair interactions. The linear hydrogen bond is found to be stronger than the bent bonds in both cases, with the difference in energy between the linear and cyclic structures being comparable in both cases although the NH bonds are generally weaker. The energy decomposition clearly demonstrates that the changes in electronic energy are quite different in the two cases due to the presence of an additional lone pair on the water molecule, and it is this effect which leads to the net stabilization of the cyclic structure for the ammonia dimer. Proton‐transfer profiles for hydrogen‐bonded ammonia complexes [NH₂ H NH₂]⁻ and [NH₃ H NH₃]⁺ were calculated. The barrier for proton transfer in [NH₃ H NH₃]⁺ is larger than that in [NH₂ H NH₂]⁻, but smaller than that in the protonated water dimer. The different bonding structures substantially affect the barrier to proton transfer, even though they are isoelectronic systems. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 73: 357–367, 1999     

The effect of water‐mediated catalysis on the intramolecular proton‐transfer reactions of the isomers of 5‐chlorouracil: a theoretical study

The geometrical structures and thermal energies (E), enthalpies (H) and Gibbs free energies (G) of 13 isomers of 5‐chlorouracil (5ClU) in the gas and water phases were investigated using the density functional theory (DFT) method at the M06‐2X/6‐311++g(3df,3pd) level. The isomers of 5ClU can be microhydrated at different molecular target sites. The mono‐ and dihydrated forms are the most stable in both the gas and water phases, and, because of the intermolecular interactions, the hydrations lead to a degree of change in the stability trend. Two types of isomerizations were considered: the internal H—O bond rotations in which the H atom rotates 180° around the C—O bond and the intramolecular proton‐transfer reactions in which an H atom is transferred between an O atom and a neighbouring N atom. The forward and backward energy barriers for isomerizations of nonhydrated 5ClU were calculated. In addition, 16 optimized transition‐state structures for water‐mediated catalysis on isomerizations of 5ClU were investigated. The forward and backward proton‐transfer energy barriers of water‐mediated catalysis on isomerizations of 5ClU were obtained. The results indicate that the catalytic effect of two H₂O molecules is much greater than that of one H₂O molecule in isomerizations of 5ClU.     

Cysteine SH and Glutamate COOH Contributions to [NiFe] Hydrogenase Proton Transfer Revealed by Highly Sensitive FTIR Spectroscopy

A [NiFe] hydrogenase (H₂ase) is a proton‐coupled electron transfer enzyme that catalyses reversible H₂ oxidation; however, its fundamental proton transfer pathway remains unknown. Herein, we observed the protonation of Cys546‐SH and Glu34‐COOH near the Ni–Fe site with high‐sensitivity infrared difference spectra by utilizing Ni‐C‐to‐Ni‐L and Ni‐C‐to‐Ni‐SI_a photoconversions. Protonated Cys546‐SH in the Ni‐L state was verified by the observed SH stretching frequency (2505 cm^?1), whereas Cys546 was deprotonated in the Ni‐C and Ni‐SI_a states. Glu34‐COOH was double H‐bonded in the Ni‐L state, as determined by the COOH stretching frequency (1700 cm^?1), and single H‐bonded in the Ni‐C and Ni‐SI_a states. Additionally, a stretching mode of an ordered water molecule was observed in the Ni‐L and Ni‐C states. These results elucidate the organized proton transfer pathway during the catalytic reaction of a [NiFe] H₂ase, which is regulated by the H‐bond network of Cys546, Glu34, and an ordered water molecule.     

Proton transfer in phenol–amine complexes: Phenol electronic effects on free energy profile in solution

Free energy profiles for the proton transfer reactions in hydrogen‐bonded complex of phenol with trimethylamine in methyl chloride solvent are studied with the reference interaction site model self‐consistent field method. The reactions in both the electronic ground and excited states are considered. The second‐order Møller‐Plesset perturbation (MP) theory or the second‐order multireference MP theory is used to evaluate the effect of the dynamical electron correlation on the free energy profiles. The free energy surface in the ground state shows a discrepancy with the experimental results for the related hydrogen‐bonded complexes. To resolve this discrepancy, the effects of chloro‐substitutions in phenol are examined, and its importance in stabilizing the ionic form is discussed. The temperature effect is also studied. In contrast to the ground state, the ππ^* excited state of phenol–trimethylamine complex exhibits the proton transfer reaction with a low barrier. The reaction is almost thermoneutral. This is attributed to the reduction of proton affinity of phenol by the ππ^* electronic excitation. We further examine the possibility of the electron–proton–coupled transfer in the ππ^* state through the surface crossing with the charge transfer type πσ^* state. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Potential Proton‐Release Channels in Bacteriorhodopsin

The protein bacteriorhodopsin pumps protons across a bacterial membrane; its pumping cycle is triggered by the photoisomerization of a retinal cofactor and involves multiple proton‐transfer reactions between intermittent protonation sites. These transfers are either direct or mediated by hydrogen‐bonded networks, which may include internal water molecules. The terminal step of the proton‐transfer sequence is the proton release from a pocket near Glu194 and Glu204 to the extracellular bulk during the transition from the L to the M photointermediate states. The polar and charged side chains connecting these two regions in the crystal structures show no structural changes between the initial bR state and the L/M states, and no intermittent protonation changes have been detected so far in this region. Based on biomolecular simulations, we propose two potential proton‐release channels, which connect the release pocket to the extracellular medium. In simulations of the L photointermediate we observe bulk water entering these channels and forming transient hydrogen‐bonded networks, which could serve as fast deprotonation pathways from the release pocket to the bulk via a Grotthuss mechanism. For the first channel, we find that the triple Arg7, Glu9, and Tyr79 acts as a valve, thereby gating water uptake and release. The second channel has two release paths, which split at the position Asn76/Pro77 underneath the release group. Here, water molecules either exchange directly with the bulk or diffuse within the protein towards Arg 134/Lys129, where the exchange with the bulk occurs.     

Deamination of the Radical Cation of the Base Moiety of 2′‐Deoxycytidine: A Theoretical Study

Five pathways leading to the deamination of cytosine (to uracil) after formation of its deprotonated radical cation are investigated in the gas phase, at the UB3LYP/6‐311G(d,p) level of theory, and in bulk aqueous solvent. The most favorable pathway involves hydrogen‐atom transfer from a water molecule to the N3 nitrogen of the deprotonated radical cation, followed by addition of the resulting hydroxyl radical to the C4 carbon of the cytosine derivative. Following protonation of the amino group (N4), the C4? N4 bond is broken with elimination of the NH₃^?+ radical and formation of a protonated uracil. The rate‐determining step of this mechanism is hydrogen‐atom transfer from a water molecule to the cytosine derivative. The associated free energy barrier is 70.2 kJ mol^?1.     

Proton dissociation and transfer in hydrated phosphoric acid clusters

The dynamics and mechanisms of proton dissociation and transfer in hydrated phosphoric acid (H₃PO₄) clusters under excess proton conditions were studied based on the concept of presolvation using the H₃PO₄–H₃O⁺–nH₂O complexes (n = 1–3) as the model systems and ab initio calculations and Born–Oppenheimer molecular dynamics (BOMD) simulations at the RIMP2/TZVP level as model calculations. The static results showed that the smallest, most stable intermediate complex for proton dissociation (n = 1) is formed in a low local‐dielectric constant environment (e.g., ε = 1), whereas proton transfer from the first to the second hydration shell is driven by fluctuations in the number of water molecules in a high local‐dielectric constant environment (e.g., ε = 78) through the Zundel complex in a linear H‐bond chain (n = 3). The two‐dimensional potential energy surfaces (2D‐PES) of the intermediate complex (n = 1) suggested three characteristic vibrational and ¹H NMR frequencies associated with a proton moving on the oscillatory shuttling and structural diffusion paths, which can be used to monitor the dynamics of proton dissociation in the H‐bond clusters. The BOMD simulations over the temperature range of 298–430 K validated the proposed proton dissociation and transfer mechanisms by showing that good agreement between the theoretical and experimental data can be achieved with the proposed rate‐determining processes. The theoretical results suggest the roles played by the polar solvent and iterate that insights into the dynamics and mechanisms of proton transfer in the protonated H‐bond clusters can be obtained from intermediate complexes provided that an appropriate presolvation model is selected and that all of the important rate‐determining processes are included in the model calculations. © 2015 Wiley Periodicals, Inc.