Mechanism of epoxide hydrolysis in microsolvated nucleotide bases adenine, guanine and cytosine: a DFT study

Six water molecules have been used for microsolvation to outline a hydrogen bonded network around complexes of ethylene epoxide with nucleotide bases adenine (EAw), guanine (EGw) and cytosine (ECw). These models have been developed with the MPWB1K-PCM/6-311++G(3df,2p)//MPWB1K/6-31+G(d,p) level of DFT method and calculated S(N)2 type ring opening of the epoxide due to amino group of the nucleotide bases, viz. the N6 position of adenine, N2 position of guanine and N4 position of cytosine. Activation energy (E(act)) for the ring opening was found to be 28.06, 28.64, and 28.37 kcal mol(-1) respectively for EAw, EGw and ECw. If water molecules were not used, the reactions occurred at considerably high value of E(act), viz. 53.51 kcal mol(-1) for EA, 55.76 kcal mol(-1) for EG and 56.93 kcal mol(-1) for EC. The ring opening led to accumulation of negative charge on the developing alkoxide moiety and the water molecules around the charge localized regions showed strong hydrogen bond interactions to provide stability to the intermediate systems EAw-1, EGw-1 and ECw-1. This led to an easy migration of a proton from an activated water molecule to the alkoxide moiety to generate a hydroxide. Almost simultaneously, a proton transfer chain reaction occurred through the hydrogen bonded network of water molecules and resulted in the rupture of one of the N-H bonds of the quaternized amino group. The highest value of E(act) for the proton transfer step of the reaction was 2.17 kcal mol(-1) for EAw, 2.93 kcal mol(-1) for EGw and 0.02 kcal mol(-1) for ECw. Further, the overall reaction was exothermic by 17.99, 22.49 and 13.18 kcal mol(-1) for EAw, EGw and ECw, respectively, suggesting that the reaction is irreversible. Based on geometric features of the epoxide-nucleotide base complexes and the energetics, the highest reactivity is assigned for adenine followed by cytosine and guanine. Epoxide-mediated damage of DNA is reported in the literature and the present results suggest that hydrated DNA bases become highly S(N)2 active on epoxide systems and the occurrence of such reactions can inflict permanent damage to the DNA.     

Fundamental reaction pathway and free energy profile for inhibition of proteasome by Epoxomicin

First-principles quantum mechanical/molecular mechanical free energy calculations have been performed to provide the first detailed computational study on the possible mechanisms for reaction of proteasome with a representative peptide inhibitor, Epoxomicin (EPX). The calculated results reveal that the most favorable reaction pathway consists of five steps. The first is a proton transfer process, activating Thr1-O(γ) directly by Thr1-N(z) to form a zwitterionic intermediate. The next step is nucleophilic attack on the carbonyl carbon of EPX by the negatively charged Thr1-O(γ) atom, followed by a proton transfer from Thr1-N(z) to the carbonyl oxygen of EPX (third step). Then, Thr1-N(z) attacks on the carbon of the epoxide group of EPX, accompanied by the epoxide ring-opening (S(N)2 nucleophilic substitution) such that a zwitterionic morpholino ring is formed between residue Thr1 and EPX. Finally, the product of morpholino ring is generated via another proton transfer. Noteworthy, Thr1-O(γ) can be activated directly by Thr1-N(z) to form the zwitterionic intermediate (with a free energy barrier of only 9.9 kcal/mol), and water cannot assist the rate-determining step, which is remarkably different from the previous perception that a water molecule should mediate the activation process. The fourth reaction step has the highest free energy barrier (23.6 kcal/mol) which is reasonably close to the activation free energy (～21-22 kcal/mol) derived from experimental kinetic data. The obtained novel mechanistic insights should be valuable for not only future rational design of more efficient proteasome inhibitors but also understanding the general reaction mechanism of proteasome with a peptide or protein.     

Mechanisms of acid decomposition of dithiocarbamates. 4. Theoretical calculations on the water-catalyzed reaction

A theoretical study of the water-catalyzed dithiocarbamic acid cleavage has been performed using N-methyl- (MeDTC) and N-phenyldithiocarbamic acid (PhDTC) as model molecules. Calculations have been carried out within the Density Functional Theory (DFT) formalism, using the B3LYP hybrid functional together with medium-sized basis sets, both in gas phase and by considering solvent effects through dielectric continuum methods. According to the results obtained, both in gas phase and in solution, MeDTC decomposes through a proton-transfer step assisted by a water molecule (this being the rate-determining step), leading to a zwitterionic intermediate, followed by a fast N-C bond-breaking process. In the case of PhDTC, the theoretical results point to a one-step mechanism in which the N-C bond breaking takes place in a concerted manner with the proton transfer. The calculated Delta Delta G(++) of the proton-transfer step for MeDTC and PhDTC is 4.0 kcal mol(-1), which is similar to the experimental values. For both compounds the water-assisted intramolecular proton transfer occurs with a twisting of the CS(2) group that inhibits the resonance of the thiocarbamic group, making the nitrogen more basic and therefore favoring the proton transfer. The difference in the torsional barrier has been calculated to be ca. 5 kcal mol(-1), and it is therefore concluded that most of the activation barrier of the reaction is due to the torsional barrier of the CS(2) group.     

New model for a theoretical density functional theory investigation of the mechanism of the carbonic anhydrase: how does the internal bicarbonate rearrangement occur?

A theoretical density functional theory (DFT, B3LYP) investigation has been carried out on the catalytic cycle of the carbonic anhydrase. A model system including the Glu106 and Thr199 residues and the "deep" water molecule has been used. It has been found that the nucleophilic attack of the zinc-bound OH on the CO(2) molecule has a negligible barrier (only 1.2 kcal mol(-1)). This small value is due to a hydrogen-bond network involving Glu106, Thr199, and the deep water molecule. The two usually proposed mechanisms for the internal bicarbonate rearrangement have been carefully examined. In the presence of the two Glu106 and Thr199 residues, the direct proton transfer (Lipscomb mechanism) is a two-step process, which proceeds via a proton relay network characterized by two activation barriers of 4.4 and 9.0 kcal mol(-1). This pathway can effectively compete with a rotational mechanism (Lindskog mechanism), which has a barrier of 13.2 kcal mol(-1). The fast proton transfer found here is basically due to the effect of the Glu106 residue, which stabilizes an intermediate situation where the Glu106 fragment is protonated. In the absence of Glu106, the barrier for the proton transfer is much larger (32.3 kcal mol(-1)) and the Lindskog mechanism becomes favored.     

Concerted or stepwise hydrogen transfer in the transfer hydrogenation of acetophenone catalyzed by ruthenium-acetamido complex: a theoretical mechanistic investigation

In this paper, the mechanism of transfer hydrogenation of acetophenone catalyzed by ruthenium-acetamido complex was studied using density function theory (DFT) method. The catalytic cycle of transfer hydrogenation consists of hydrogen transfer (HT) step and dehydrogenation (DH) step of isopropanol (IPA). Inner sphere mechanism (paths 1 and 7) and outer sphere mechanism (paths 2-6) in HT step are fully investigated. Calculated results indicate that DH step of IPA (from (i)1 to (i)2) is the rate-determining step in the whole catalytic cycle, which has a potential energy barrier of 16.2 kcal/mol. On the other hand, the maximum potential energy barriers of paths 1-7 in the HT step are 5.9, 12.7, 24.4, 16.8, 23.7, 7.2, and 6.1 kcal/mol, respectively. The inner sphere pathways (paths 1 and 7) are favorable hydrogen transfer modes compared with outer sphere pathways, and the proton transferred to the oxygen atom of acetophenone comes from the hydroxyl group but not from amino group of acetamido ligand. Those theoretical results are in agreement with experimental report. However, in view of this DFT study in the inner sphere mechanism of HT step, hydride transfer and proton transfer are concerted and asynchronous hydrogen transfer but not a stepwise one, and hydride transfer precedes proton transfer in this case.     

DFT study of the glutathione peroxidase-like activity of phenylselenol incorporating solvent-assisted proton exchange

Modeling of the glutathione peroxidase-like activity of phenylselenol has been accomplished using density-functional theory and solvent-assisted proton exchange (SAPE). SAPE is a modeling technique intended to mimic solvent participation in proton transfer associated with chemical reaction. Within this method, explicit water molecules incorporated into the gas-phase model allow relay of a proton through the water molecules from the site of protonation in the reactant to that in the product. The activation barriers obtained by SAPE for the three steps of the GPx-like mechanism of PhSeH fall within the limits expected for a catalytic system at physiological temperatures (DeltaG(1)++ = 19.1 kcal/mol; DeltaG(2)++= 6.6 kcal/mol; G(3)++ = 21.7 kcal/mol) and are significantly lower than studies which require direct proton transfer. The size of the SAPE network is also considered for the model of the reduction of the selenenic acid, step 2 of the GPx-like cycle. Use of a four-water network better accommodates the reaction pathway and reduces the activation barrier by 5 kcal/mol over the two-water model.     

Computational study of phosphatase activity in soluble epoxide hydrolase: high efficiency through a water bridge mediated proton shuttle

Recently, a new branch of fatty acid metabolism has been opened by the novel phosphatase activity found in the N-terminal domain of the, hence bifunctional, soluble epoxide hydrolase (sEH). Importantly, this finding has also provided a new site for drug targeting in sEH's activity regulation. Classical MD and hybrid Car-Parrinello QM/MM calculations have been performed to investigate the reaction mechanism of the phosphoenzyme intermediate formation in the first step of the catalysis. The results support a concerted multi-event reaction mechanism: (1) a dissociative in-line nucleophilic substitution for the phosphoryl transfer reaction; (2) a double proton transfer involved in the formation of a good leaving group in the transition state. The presence of a water bridge in the substrate/enzyme complex allowed an efficient proton shuttle, showing its key role in speeding up the catalysis. The calculated free energy of the favored catalytic pathway is approximately 19 kcal/mol, in excellent agreement with experimental data.     

Ab initio model study on acetylcholinesterase catalysis: potential energy surfaces of the proton transfer reactions

Ab initio molecular orbital (MO) and hybrid density functional theory (DFT) calculations have been applied to the initial step of the acylation reaction catalyzed by acetylcholinesterase (AChE), which is the nucleophiric addition of Ser200 in catalytic triads to a neurotransmitter acetylcholine (ACh). We focus our attention mainly on the effects of oxyanion hole and Glu327 on the potential energy surfaces (PESs) for the proton transfer reactions in the catalytic triad Ser200-His440-Glu327. The activation barrier for the addition reaction of Ser200 to ACh was calculated to be 23.4 kcal/mol at the B3LYP/6-31G(d)//HF/3-21G(d) level of theory. The barrier height under the existence of oxyanion hole, namely, Ser200-His440-Glu327-ACh-(oxyanion hole) system, decreased significantly to 14.2 kcal/mol, which is in reasonable agreement with recent experimental value (12.0 kcal/mol). Removal of Glu327 from the catalytic triad caused destabilization of both energy of transition state for the reaction and tetrahedral intermediate (product). PESs calculated for the proton transfer reactions showed that the first proton transfer process is the most important in the stabilization of tetrahedral intermediate complex. The mechanism of addition reaction of ACh was discussed on the basis of theoretical results.     

A novel hydrogen migration of dialkylphosphonic acid esters using electrospray ionization tandem mass spectrometry

In this paper, attention is focused on analysis of the fragmentation of α-hydroxy-β-amino phosphonate esters designed as inhibitors of protein kinase A. An interesting proton migration mechanism in the cleavage of the P-C bond is investigated by electrospray ionization tandem mass spectrometry. A possible rearrangement mechanism is proposed and verified by high-resolution mass spectra using isotope deuterium/hydrogen-exchange technology and additionally checked by detailed DFT calculation based on Gaussian software. The result clearly indicates that this mechanism proceeds by a five-membered ring concerted transition state with activation energy 11.3 kcal mol(-1) for the compound 3f. The overall reaction is endothermic with an energy 13.2 kcal mol(-1). The effect of different substituents and different metal ions for rearrangement of these esters is studied by experiment and theory. It is concluded that this rearrangement process is energetically unfavorable and hence only occurs in the mass spectrometer.     

Quantum chemical study of the mechanism of action of vitamin K carboxylase (VKC). IV. Intermediates and transition states

We studied proposed steps for the enzymatic formation of gamma-carboxyglutamic acid by density functional theory (DFT) quantum chemistry. Our results for one potentially feasible mechanism show that a vitamin K alkoxide intermediate can abstract a proton from glutamic acid at the gamma-carbon to form a carbanion and vitamin K epoxide. The hydrated carbanion can then react with CO2 to form gamma-carboxyglutamic acid. Computations at the B3LYP/6-311G** level were used to determine the intermediates and transition states for the overall process. The activation free energy for the gas-phase path is 22 kcal/mol, with the rate-limiting step for the reaction being the attack of the carbanion on CO2. Additional solvation studies, however, indicate that the formation of the carbanion step can be competitive with the CO2 attack step in high-dielectric systems. We relate these computations to the entire vitamin K cycle in the blood coagulation cascade, which is essential for viability of vertebrates.     

A theoretical examination of the acid-catalyzed and noncatalyzed ring-opening reaction of an oxirane by nucleophilic addition of acetate. Implications to epoxide hydrolases

Ab initio and density functional calculations have been performed to gain a better understanding of the epoxide ring-opening reaction catalyzed by epoxide hydrolase. The S(N)2 reaction of acetate with 1S,2S-trans-2-methylstyrene oxide to provide the corresponding diol acetate ester was studied with and without general-acid catalysis. MP2 and DFT (B3LYP) calculations predict, for the noncatalyzed reaction, a central barrier of approximately 20-21 kcal/mol separating the reactants from products depending on which carbon center in the epoxide is undergoing attack. From these gas-phase reactions the immediate alkoxide products are not energetically far below their associated transition states such that the reaction is predicted to be endothermic. Inclusion of aqueous solvation effects via a polarizable continuum model predicts the activation barrier to increase by almost 10 kcal/mol due to the solvation of the acetate ion nucleophile. The activation barrier for the epoxide ring-opening reaction is reduced to approximately 10 kcal/mol when phenol, as the general-acid catalyst, is included in the gas-phase calculations. This is due to the immediate product being the neutral ester rather than the corresponding alkoxide. The transition state in the general-acid-catalyzed reaction is earlier than that for the noncatalyzed reaction and the reaction is highly exothermic. Molecular mechanics calculations of 1S,2S-trans-2-methylstyrene oxide in the active site of murine epoxide hydrolase show two possible binding conformations. Both conformers have the epoxide oxygen forming hydrogen bonds with the acidic hydrogens of the catalytic tyrosines (Tyr381 and Tyr465). These two conformations likely lead to different products since the nucleophile (Asp333-CO(2)(-)) is positioned to react with either carbon center in the epoxide.     

A Marcus treatment of rate constants for protonation of ring-substituted alpha-methoxystyrenes: intrinsic reaction barriers and the shape of the reaction coordinate

Rate and equilibrium constants were determined for protonation of ring-substituted -methoxystyrenes by hydronium ion and by carboxylic acids to form the corresponding ring-substituted alpha-methyl alpha-methoxybenzyl carbocations at 25 degrees C and I = 1.0 (KCl). The thermodynamic barrier to carbocation formation increases by 14.5 kcal/mol as the phenyl ring substituent(s) is changed from 4-MeO- to 3,5-di-NO2-, and as the carboxylic acid is changed from dichloroacetic to acetic acid. The Br?nsted coefficient alpha for protonation by carboxylic acids increases from 0.67 to 0.77 over this range of phenyl ring substituents, and the Br?nsted coefficient beta for proton transfer increases from 0.63 to 0.69 as the carboxylic acid is changed from dichloroacetic to acetic acid. The change in these Br?nsted coefficients with changing reaction driving force, (inverted theta)alpha/ (inverted theta) deltaG(av) degrees=(inverted theta)beta/(inverted theta)delta G(av) degrees= 1/8lambda = 0.011, is used to calculate a Marcus intrinsic reaction barrier of lambda= 11 kcal/mol which is close to the barrier of 13 kcal/mol for thermoneutral proton transfer between this series of acids and bases. The value of alpha= 0.66 for thermoneutral proton transfer is greater than alpha= 0.50 required by a reaction that follows the Marcus equation. This elevated value of beta may be due to an asymmetry in the reaction coordinate that arises from the difference in the intrinsic barriers for proton transfer at the oxygen acid reactant and resonance-stabilized carbon acid product.     

Theoretical investigation on mechanism of asymmetric Michael addition of malononitrile to chalcones catalyzed by Cinchona alkaloid aluminium(III) complex

The mechanism of Michael addition of malononitrile to chalcones catalyzed by Cinchona alkaloid aluminium(III) complex has been investigated by DFT and ONIOM methods. Calculations indicate that the reaction proceeds through a dual activation mechanism, in which Al(III) acts as a Lewis acid to activate the electrophile α,β-unsaturated carbonyl substrate while the tertiary amine in the Cinchona alkaloid works as a Lewis base to promote the activation of the malononitrile and deprotonation. A stepwise pathway involving C-C bond formation followed by proton transfer from the catalyst to the carbonyl substrate is adopted, and latter step is predicted to be the rate-determining-step in the reaction with an energy barrier of 12.4 kcal mol(-1). In the absence of the Al(III)-complex, a Cinchona alkaloid activates the carbonyl substrate by a hydrogen bonding of the hydroxyl group, involving a higher energy barrier of 30.4 kcal mol(-1). The steric repulsion between the phenyl group attached to the carbonyl group in the chalcone and isopropoxyl groups of the Al(III)-complex may play an important role in the control of stereoselectivity. The π-π stacking effect between the quinuclidine ring of the quinine and the phenyl group of the chalcones may also help the stabilization of the preferred molecular complex. These results are in agreement with experimental observations.     

2-hydroxypyridine <--> 2-pyridone tautomerization: catalytic influence of formic acid

A 1:1 hydrogen-bonded complex between 2-pyridone and formic acid has been characterized using laser-induced-fluorescence excitation and dispersed fluorescence spectroscopy in a supersonic jet expansion. Under the same expansion condition, the fluorescence signal of the tautomeric form of the complex (2-hydroxypyridine...formic acid) is absent, although both the bare tautomeric molecules exhibit well-resolved laser-induced-fluorescence spectra. Quantum chemistry calculation at the DFT/B3LYP/6-311++G** level predicts that in the ground electronic state the activation barrier for tautomerization from hydroxy to keto form in bare molecules is very large (approximately 34 kcal/mol). However, the process turns out to be nearly barrierless when assisted by formic acid, and double proton transfer occurs via a concerted mechanism.     

Experimental and computational studies of hydrogen bonding and proton transfer to [Cp*Fe(dppe)H

The present contribution reports experimental and computational investigations of the interaction between [Cp*Fe(dppe)H] and different proton donors (HA). The focus is on the structure of the proton transfer intermediates and on the potential energy surface of the proton transfer leading to the dihydrogen complex [Cp*Fe(dppe)(H2)]+. With p-nitrophenol (PNP) a UV/Visible study provides evidence of the formation of the ion-pair stabilized by a hydrogen bond between the nonclassical cation [Cp*Fe(dppe)(H2)]+ and the homoconjugated anion ([AHA]-). With trifluoroacetic acid (TFA), the hydrogen-bonded ion pair containing the simple conjugate base (A-) in equilibrium with the free ions is observed by IR spectroscopy when using a deficit of the proton donor. An excess leads to the formation of the homoconjugated anion. The interaction with hexafluoroisopropanol (HFIP) was investigated quantitatively by IR spectroscopy and by 1H and 31P NMR spectroscopy at low temperatures (200-260 K) and by stopped-flow kinetics at about room temperature (288-308 K). The hydrogen bond formation to give [Cp*Fe(dppe)H]HA is characterized by DeltaH degrees =-6.5+/-0.4 kcal mol(-1) and DeltaS degrees = -18.6+/-1.7 cal mol(-1) K(-1). The activation barrier for the proton transfer step, which occurs only upon intervention of a second HFIP molecule, is DeltaH(not equal) = 2.6+/-0.3 kcal mol(-1) and DeltaS(not equal) = -44.5+/-1.1 cal mol(-1) K(-1). The computational investigation (at the DFT/B3 LYP level with inclusion of solvent effects by the polarizable continuum model) reproduces all the qualitative findings, provided the correct number of proton donor molecules are used in the model. The proton transfer process is, however, computed to be less exothermic than observed in the experiment.     

Theoretical study on the nitration of methane by acyl nitrate catalyzed by H-ZSM5 zeolite

A theoretical study on the nitration of methane by acyl nitrate catalyzed by HZSM-5 zeolite is reported. The zeolite was represented by a "double ring" 20T cluster. The calculations were performed at the DFT/X3LYP/6-31G** and MP2/6-31G** levels. The first step of the mechanism involves the protonation of the acyl nitrate by the zeolite and the formation of a nitronium-like ion. The reaction proceeds through a concerted step with the attack of the methane molecule by the nitronium-like ion and the simultaneous transfer of a proton from the methane molecule to the zeolite, thus reconstructing the acidic site. The activation energies for the first and second steps of this reaction are, respectively, 14.09 and 10.14 kcal/mol at X3LYP/6-31G** level and 16.68 and 13.85 kcal/mol at the MP2/6-31G**.     

Mechanistic study on the gold-catalyzed C-S bond formation of α-thioallenes to form 2,5-dihydrothiophenes

The reaction mechanism of the AuCl-catalyzed reaction of the α-thioallenes to give 2,5-dihydrothiophenes has been computationally studied using DFT (B3LYP/6-31G*, SDD for Au). Calculations indicate the complexation of α-thioallene with AuCl occurs preferentially at the distal double bond, followed by the C-S bond formation, the proton transfer from the sulfur to the carbon "b", and the [1,2]-hydride shift to give the 2,5-dihydrothiophene gold complex. The proton transfer is the rate-limiting step with very high activation energy in the gas phase. In the presence of one water molecule, the activation free energy of the proton transfer was lowered by as much as 19.9 kcal/mol. Furthermore, one dichloromethane molecule stabilized all of the transition structures by its hydrogen bonds.     

New insights into the mechanism of the Schiff base hydrolysis catalyzed by type I dehydroquinate dehydratase from S. enterica: a theoretical study

The reaction pathway of Schiff base hydrolysis catalyzed by type I dehydroquinate dehydratase (DHQD) from S. enterica has been studied by performing molecular dynamics (MD) simulations and density functional theory (DFT) calculations and the corresponding potential energy profile has also been identified. On the basis of the results, the catalytic hydrolysis process for the wild-type enzyme consists of three major reaction steps, including nucleophilic attack on the carbon atom involved in the carbon-nitrogen double bond of the Schiff base intermediate by a water molecule, deprotonation of the His143 residue, and dissociation between the product and the Lys170 residue of the enzyme. The remarkable difference between this and the previously proposed reaction mechanism is that the second step here, absent in the previously proposed reaction mechanism, plays an important role in facilitating the reaction through a key proton transfer by the His143 residue, resulting in a lower energy barrier. Comparison with our recently reported results on the Schiff base formation and dehydration processes clearly shows that the Schiff base hydrolysis is rate-determining in the overall reaction catalyzed by type I DHQD, consistent with the experimental prediction, and the calculated energy barrier of ～16.0 kcal mol(-1) is in good agreement with the experimentally derived activation free energy of ～14.3 kcal mol(-1). When the imidazole group of His143 residue is missing, the Schiff base hydrolysis is initiated by a hydroxide ion in the solution, rather than a water molecule, and both the reaction mechanism and the kinetics of Schiff base hydrolysis have been remarkably changed, clearly elucidating the catalytic role of the His143 residue in the reaction. The new mechanistic insights obtained here will be valuable for the rational design of high-activity inhibitors of type I DHQD as non-toxic antimicrobials, anti-fungals, and herbicides.     

Ab initio and density functional theory evidence on the rate-limiting step in the Morita-Baylis-Hillman reaction

The first ab initio and DFT studies on the mechanism of the MBH reaction show that the rate-limiting step involves an intramolecular proton transfer in the zwitterionic intermediate generated by the addition of enolate to electrophile. The activation barrier for the C-C bond-formation is found to be 20.2 kcal/mol lower than the proton-transfer step for the MBH reaction between methyl vinyl ketone and benzaldehyde catalyzed by DABCO.     

Reaction mechanism and tautomeric equilibrium of 2-mercaptopyrimidine in the gas phase and in aqueous solution: a combined Monte Carlo and quantum mechanics study

A combined Monte Carlo and quantum mechanical study was carried out to analyze the tautomeric equilibrium of 2-mercaptopyrimidine in the gas phase and in aqueous solution. Second- and fourth-order M?ller-Plesset perturbation theory calculations indicate that in the gas phase thiol (Pym-SH) is more stable than the thione (Pym-NH) by ca. 8 kcal/mol. In aqueous solution, thermodynamic perturbation theory implemented on a Monte Carlo NpT simulation indicates that both the differential enthalpy and Gibbs free energy favor the thione form. The calculated differential enthalpy is DeltaH(SH)(-->)(NH)(solv) = -1.7 kcal/mol and the differential Gibbs free energy is DeltaG(SH)(-->)(NH)(solv) = -1.9 kcal/mol. Analysis is made of the contribution of the solute-solvent hydrogen bonds and it is noted that the SH group in the thiol and NH group in the thione tautomers act exclusively as a hydrogen bond donor in aqueous solution. The proton transfer reaction between the tautomeric forms was also investigated in the gas phase and in aqueous solution. Two distinct mechanisms were considered: a direct intramolecular transfer and a water-assisted mechanism. In the gas phase, the intramolecular transfer leads to a large energy barrier of 34.4 kcal/mol, passing through a three-center transition state. The proton transfer with the assistance of one water molecule decreases the energy barrier to 17.2 kcal/mol. In solution, these calculated activation barriers are, respectively, 32.0 and 14.8 kcal/mol. The solvent effect is found to be sizable but it is considerably more important as a participant in the water-assisted mechanism than the solvent field of the solute-solvent interaction. Finally, the calculated total Gibbs free energy is used to estimate the equilibrium constant.