It is important to develop an accurate “dual-level” approach for the prediction of the activation free energy barriers of reactions in solution phase, particularly in binary mixed solvent and under “on water” condition, in which the result obtained by the semiempirical method-based quantum mechanics/molecular mechanics/Monte Carlo (QM/MM/MC) simulation is improved by using a high level of theory to the QM section in the gas phase. In this work, several density functional theory methods MP2/CBS and CCSD(T)/CBS with extrapolation to the complete basis set limit have been selected to calculate the free energies of activation in gas phase for the 1,3-dipolar cycloadditions of the phthalazinium dicyanomethanide 1 with three dipolarophiles, methyl vinyl ketone, methyl acrylate, and styrene as case systems. The suitability of those methods to reproduce the accurate free energy of activation barriers has been evaluated by comparing the computed ΔGsolution≠ values with the experimental ones in pure solvents (water and acetonitrile) as well as in binary water–acetonitrile mixed solvents with mol fractions of water of 0.619 and 0.9, respectively. In short, the best agreement is achieved with the TPSSKCIS and TPSSTPSS functionals with 6-311 +G(d,p) basis set, resulting in the root-mean-squared deviation (RMSD) of less than 1.5 kcal/mol. The ΔGsolution≠ values under “on water” condition are also predicted. Our results indicate that the “dual-level” approach using appropriate functional is useful for the investigation of dynamical properties of reactions in solution.

Doyle et al. [ J. Am. Chem. Soc. 2013, 135, 1244−1247] recently reported an efficient catalyst-controlled chemoselectivity of competitive 1,2-C→C, −O→C, and −N→C migrations from β-methylene-β-silyloxy-β-amido-α-diazoacetates using dirhodium or copper catalysts. With the aid of density functional theory calculations, the present study systematically probed the mechanism of the aforementioned reactions and the origins of the catalyst-controlled chemoselectivity. Similar to the method reported in the literature, simplified catalyst models Rh2(O2CH)4 and Rh2(N-methylformamide)4 have been used in our initial calculations. However, using the Rh2(O2CH)4 model could not describe the energies of all possible pathways, and high selectivity of three competitive migrations could not be achieved. In order to appropriately describe this 1,2-migration system, real catalyst models Rh2(cap)4, Rh2(esp)2, and CuPF6 have been employed. It was found that the steric and electronic effects of ligands significantly influence the free energy barrier, which ultimately changes the chemoselectivity. In the CuPF6 system, the electronic effects, coupled with the steric factor, give a qualitative explanation for the exclusive chemoselectivity of 1,2-N→C migration over 1,2-C→C or −O→C migration. On the other hand, the bulky ligands of dirhodium catalysts result in the significant steric hindrance around the dirhodium centers and withdrawal of the empty space around the bulky −OTBS group. By analyzing the divergence of three different migration transition states using the distortion/interaction and natural bond orbital analyses, it was found that the 1,2-N→C migration will suffer from a high free energy barrier because of the steric repulsion between the carbonyl group and the carbonyl oxygen of the pyrazolidinone ring. For 1,2-C→C and −O→C migrations, changing the ligands of dirhodium catalysts can change the electronic properties of carbenes, and that is the reason for controlling the major product by changing the dirhodium catalysts. The mechanistic proposal is supported by the calculated chemoselectivities, which are in good agreement with the experimental results.Keywords: 1,2-migration; chemoselectivity; copper catalyst; DFT calculations; dirhodium catalyst; distortion/interaction analysis; mechanistic studies; metal−carbene

The density functional theory(DFT) was used to investigate the adsorptions of carbon dioxide(CO2) on kaolinite surfaces and the influences of Na+ and H2O on the adsorption. Both cluster and periodic models of kaolinite were considered. The calculated results indicate that stable complexes can be formed between adsorbed CO2 and the surfaces of kaolinite in the presence or absence of sodium cation and water molecule. The Al―O octahedral surface has a larger adsorption affinity for CO2 than the Si―O tetrahedral surface of kaolinite because the hydroxyl groups of kaolinite Al―O surface present more activity than the basal O atoms of the Si―O tetrahedral surface in the intermolecular interactions. The existence of exchangeable sodium cations exerts the significant effect on the adsorption of CO2 with the dramatic increase of the adsorption energy, while the presence of water molecule decreases the adsorption strength insignificantly. The calculated Gibbs free energies of the adsorption reveal that the adsorptions of CO2 on all the investigated kaolinite surfaces are feasible thermodynamically in the gas phase. Surface free energy was calculated to provide the predictions of the surface stability as a function of temperature.

The origin of enantioselectivity in the dirhodium-catalyzed [3 + 2]-cycloaddition of nitrone and vinyldiazoacetate has been investigated using dispersion-corrected density functional theory. Taking a more realistic account of bulky ligands in models of the dirhodium catalyst when investigating its catalytic behavior is crucial for describing the effects resulting from a high level of asymmetric induction. More than one active site can be located and the extra reactivity is provided by an electron-donation interaction between the substrate and an additional Rh2L4 catalyst.

•We predicted selective inhibitors of MMP-3 and MMP-9 using machine learning methods.•Random forest and support vector machine were employed to construct classification models.•Feature selection approach was applied to extract a set of the most appropriate descriptors.•RF model is slightly better than the one of SVM.•The virtual screening of MMP-1, -3 and -9 inhibitors against the SCdatabase were performed.Over-expression of matrix metalloproteinases (MMPs) has been linked to a variety of serious pathological disorders. Methods of predicting and screening vigorous and selective MMP inhibitors are urgently needed for facilitating the design and development of novel therapeutic agents. Two machine learning methods, support vector machine (SVM) and random forest (RF), were explored to develop prediction models for diversely structural selective inhibitors of MMP-3 over MMP-1 and MMP-9 versus MMP-1 in this work, individually. The developed models were validated by testing sets and external independent validation sets, showing satisfactory performance. The physicochemical properties most extensively concerned with MMP-3 and MMP-9 selective inhibition were extracted from a set of 189 descriptors by feature selection methods, which are capable of competently describing most of the molecular features of these inhibitors. The molecular descriptors most relevant to MMP-1 inhibitors were also derived from these 189 features. All those properties provide an excellent analytical perspective to explain the similarities and differences to MMP-1, MMP-3 and MMP-9 inhibitors in structure or function. Finally, the virtual screening of MMP-1, MMP-3 and MMP-9 inhibitors against the SCdatabase were separately performed based on the RF model which is slightly better than the SVM method, resulting in 110 potential hit candidates for MMP-3 over both MMP-1 and MMP-9, 23 hits for MMP-9 versus both MMP-1 and MMP-3, and 80 hits for MMP-3 and MMP-9.

The mechanism of the transamidation reaction between carboxamides and benzylamine catalysed by L-proline in toluene was investigated using density functional theory (DFT) at the M06/SMD/6-311+G(2d,p)//M06/6-31+G(d,p) level. The calculations reveal that the reaction proceeds through a stepwise mechanism, in which the L-proline acts as a Lewis base to activate acetamide. The hydrolysis step is predicted to be the rate-determining step (RDS) in the reaction with an energy barrier of 26.0 kcal mol−1. The comparison of the catalytic effect between the acetamide with benzylamine in three different solvents including toluene, EtOH, and H2O, suggests that toluene exhibits higher catalytic efficiency for the transamidation, and less polar solvents are favourable for the reaction, which is in good agreement with the experimental observations.

•The adsorption of H2 on Ca decorated BC2N doped by B or C was studied theoretically. by the first-principles method.•The spin-polarized local density approximation (LDA) with CA-PZ functional was used.•Several adsorption sites of H2 on Ca–BC2N models were systematically explored.•The practical usable capacities are 8.36 and 8.38 wt% for the H11 configurations.•Ca decorated BC2NBC and BC2NCN can work as high-capacity H2 storage materials.Hydrogen adsorption and storage on calcium-decorated BC2N sheets doped by Boron or Carbon were investigated using the first-principles calculations. Unlike the weak bond between Ca atoms and pristine BC2N, doping boron or carbon atoms on BC2N sheet can significantly strengthen the Ca atoms on the BC2N, especially for BC2NBC and BC2NCN. It is observed that Ca decorated BC2NBC and BC2NCN possess strong donation and back-donation of Ca with the sheets, which is responsible for enhanced binding energy to eliminate the clustering problem. Up to four hydrogen molecules can stably attach to a Ca atom with an average adsorption energy of ∼0.3 eV, which is in the range that permits hydrogen recycling at ambient conditions. The Ca decorated BC2NBC and BC2NCN complexes can work as high-capacity hydrogen storage materials with the practical usable capacities of 8.36 wt% and 8.38 wt%, respectively.

The 1,3-dipolar cycloaddition reaction between pyridazinium dicyanomethanide 1 and ethyl vinyl ketone (EVK) has been reported to be a concerted mechanism based on gas-phase ab initio calculations. Our current investigation of this 1,3-dipolar cycloaddition reaction in water, methanol, acetonitrile, H2O–CH3CN, and CH3OH–CH3CN mixtures using novel two-dimensional potentials of mean force (2-D PMF) calculations coupled to QM/MM simulations predicts an alternative free energy surface that supports a stepwise mechanism. The results for the kinetic effect are uniformly in close accord with experimental data and reflect a trigger point for the exponential rate rise in water–acetonitrile mixture. When methanol replaced water, the rate enhancements are more gradual, and there is no trigger point. Calculations in pure solvents and their mixtures at 25 °C and with pure water and acetonitrile at 37 °C indicate that the secondary bridging H-bonding from the first water molecules is necessary for the exponential rate enhancements, which is strong supported by the experimental results. This work provides new insight into solvent effects on 1,3-dipolar cycloaddition reaction.

An “on water” environment, describing the reactions with insoluble reactants in water, has been reported to give high yields of products compared to organic solvents. The 1,3-dipolar cycloadditions of phthalazinium dicyanomethanide 1 with three different dipolarophiles, methyl vinyl ketone (MVK), methyl acrylate (MAC), and styrene (STY), have been investigated using QM/MM calculations in water, acetonitrile, and acetonitrile–water solvent mixtures, as well as at the vacuum–water interface. Monte Carlo statistical mechanics simulations utilizing the free-energy perturbation theory and PDDG/PM3 for the QM method have been used. The transition structures for all three reactions do not show large variations among different solvents. However, the calculated free energies of activation at the interface are found to be higher than those calculated in bulk water. Computed energy pair distributions and radial distribution functions reveal a uniform loss of hydrogen bonds for the reactants and transitions states in progressing from bulk water to the vacuum–water interface. The hydrophobic effects in the reactions of 1 with MVK and MAC are similar for both, and weaker than the effect in the reaction with STY. According to the results in water–acetonitrile mixtures at different molar ratios, it is clear that the special hydrogen bonding effects are the main reason which leads to the rapid rate enhancement in progressing from a water–acetonitrile molar ratio of 0.9:0.1 to pure water. New insights into solvent effects for 1,3-dipolar cycloadditions are presented herein.

•We explored the Machine Learning (ML) methods for predicting H1N1 inhibitors.•Two coupled GA-PLS and GA-SVM methods were employed to construct QSAR models.•GA-PLS method was applied for extracting a set of the most appropriate descriptors.•SVM gives more accurate predicted values for H1N1 inhibitory activity than PLS.•It is shown that SVM is useful for facilitating the discovery of H1N1 inhibitors.The quantitative structure–activity relationship (QSAR) for the prediction of the activity of two different scaffolds of 108 influenza neuraminidase A/PR/8/34 (H1N1) inhibitors was investigated. A feature selection method, which combines Genetic Algorithm with Partial Least Square (GA–PLS), was applied to select proper descriptor subset for QSAR modeling in a linear model. Then Genetic Algorithm-Support Vector Machine coupled approach (GA–SVM) was first used to build the nonlinear models with nine GA–PLS selected descriptors. With the SVM regression model, the corresponding correlation coefficients (R) of 0.9189 for the training set, 0.9415 for the testing set and 0.9254 for the whole data set were achieved respectively. The two proposed models gained satisfactory prediction results and can be extended to other QSAR studies.The Genetic Algorithm combining respectively with Partial Least Square (GA–PLS) and Support Vector Machine (GA–SVM) were used to study the quantitative structure–activity relationship on influenza neuraminidase A/PR/8/34 (H1N1) inhibitors.

•The adsorption of CO2 on coal model surface was studied by the DFT-D3 method.•The BLYP-D3/6-311++G(d,p) method was selected compared with CCSD(T)/CBS method.•Several adsorption sites and orientations of CO2 on coal models were explored.•Increasing the size of the π-system leads to an increase in binding energy.The adsorption of carbon dioxide on N-containing molecular segment models of coal (2-methylpyridine, C13H9N, C23H12N, and N-doped graphenes) has been investigated by the density functional theory including dispersion correction (DFT-D3) method. Four kinds of DFT-D3 methods (BLYP-D3, PBE-D3, BP86-D3 and TPSS-D3 functionals) were used to calculate the binding energy of CO2 with 2-methylpyridine, and the results were examined by benchmark value which was calculated by the coupled-cluster calculation with singles, doubles, and perturbative triple excitations [CCSD(T)] method in the complete basis set (CBS) limit. Due to its best performance, the BLYP-D3 functional was selected to investigate the binding of CO2 to N-doped hydrocarbon clusters (C13H9N and C23H12N). The adsorption of CO2 onto several different adsorption sites and orientations on coal surface models were systematically explored. Our research indicates that increasing the size of the π-system leads to an increase in binding energy. In the C13H9N···CO2 complex, the binding energy is in the range of − 2.36–− 2.66 kcal/mol, while C23H12N···CO2 complex has the results of − 3.24–− 3.56 kcal/mol. We also considered the adsorption of CO2 on the periodic monolayer and bilayer N-doped graphenes. However, as no significant intermolecular charge transfer exists in the physisorption models, the effect of finite ring size on the binding energies in complexes was not obvious.

The density functional theory including dispersion correction (DFT-D3) has been used to investigate the adsorption of methane on carbon models of coal surface, including C6H8, pyrene, and coronene. For the small model complex C6H8–CH4, the interaction energies obtained using four kinds of the functionals, BLYP-D3, TPSS-D3, BP86-D3, and PBE-D3, were benchmarked against the best available result that was provided by the complete basis set (CBS) limit of CCSD(T) method, and the BLYP-D3 functional with the best performance was selected to treat the remained larger systems. Several adsorption positions and orientations of CH4 on the hydrocarbon clusters were systematically considered. Our results indicated that the interaction energy in the complex increases as the size of the complex increases and the up configuration of CH4 (with the hydrogen tripod directed to the surface) adsorbed on pyrene and coronene is greatly preferred when compared with both the down and bidentate configurations. The center adsorption site above the six-membered ring is preferred by the methane molecule adsorbed on coronene. It was shown that in coronene–methane model the interaction energies of −3.17 to −3.32 kcal/mol and the molecular distances of 3.36–3.39 Å obtained from the BLYP-D3 calculations are close to the values available in experiment for the binding of methane on graphite and can provide the accurate prediction to those in the coal surface–methane complex.Graphical abstractHighlights► The adsorption of CH4 on coal model surface was studied by the DFT-D3 method. ► The BLYP-D3/aug-cc-pVTZ method was selected after compared with CCSD(T)/CBS method. ► We find the up mode of methane of the investigated complexes is preferred one. ► The CH4–coronene complex can describe the interaction model in coal–methane system. ► Eint difference between the BLYP-D3 and experimental results is within 0.10 kcal/mol.

The possible catalytic effects of 2-pyridone and its tautomeric form 2-hydroxypyridine on the aminolysis reaction of p-nitrophenyl acetate with n-butylamine have been theoretically studied at the B3LYP/6-31+G(d,p) level of theory. Solvent effect of chloroform is assessed using the MP2/CPCM/6-31++G(d,p)//B3LYP/6-31+G(d,p) method. In our work, three possible mechanisms are considered for the title reaction. The first mechanism is concerted via a four-membered ring transition state assisted by supramolecular effect of the catalyst. The second mechanism undergoes two sequential steps, where the intermolecular proton transfer bridged by the catalyst is the rate-determining process. And the third mechanism, forming a zwitterionic intermediate, is also stepwise via three steps, nucleophilic addition, double-proton transfer, and elimination of leaving group. Our calculations give a detailed picture of the whole stepwise pathway through zwitterionic intermediates for the first time, and indicate that this mechanism is the most favored pathway both in the gas phase and in chloroform.Graphical abstractDFT studies are carried out on the possible catalytic effects of 2-pyridone and its tautomeric form 2-hydroxypyridine on the aminolysis reaction of p-nitrophenyl acetate with n-butylamine in chloroform. The stepwise pathway through zwitterionic intermediates is the most favorable.Highlights► Three possible mechanisms for the title reaction are considered. ► The stepwise pathway through zwitterionic intermediates is the most favored. ► 2-Pyridone accelerates the reaction with supramolecular effect and proton shuttle.

The efficient formation of 5-methylcytosine glycol (mCg) and its facile deamination to thymine glycol (Tg) may account for the prevalent C → T transition mutation found at methylated CpG site (mCpG) in human p53 gene, a hallmark for many types of human tumors. In this work, the hydrolytic deamination of mCg was investigated at the MP2 and B3LYP levels of theory using the 6-311G(d,p) basis set. In the gas phase, three pathways were explored, paths A–C, and it indicates that the direct deamination of mCg with H2O by either pathway is unlikely because of the high activation free energies involved in the rate-determining steps, the formation of the tetrahedral intermediate for paths A and B as well as the formation of the Tg tautomer for path C. In aqueous solution, the role of the water molecules in the deamination of mCg with H2O was analyzed in two separate parts: the direct participation of one water molecule in the reaction pathway, called the water-assisted mechanism; and the complementary participation of the aqueous solvation. The water-assisted mechanism was carried out for mCg and the cluster of two water molecules by quantum mechanical calculations in the gas phase. This indicates that the presence of the auxiliary water molecule significantly contributes to decreasing all the activation free energies. The bulk solution effect on the water-assisted mechanism was included by free energy perturbation implemented on Monte Carlo simulations, which is found to be substantial and decisive in the deamination mechanism of mCg. In this case, the water-assisted path A is the most plausible mechanism reported for the deamination of mCg, where the calculated activation free energy (22.6 kcal mol−1 at B3LYP level of theory) agrees well with the experimentally determined activation free energy (24.8 kcal mol−1). The main striking results of the present DFT computational study which is in agreement with previous experimental data is the higher rate of deamination displayed by mCg residues with respect to 5-methylcytosine (mC) bases, which supports that the deamination of mCg contributes significantly to the C → T transition mutation at mCpG dinucleotide site.

Computational investigations on the acid-promoted hydrolysis of 2-aryl-4,4-dimethyloxazolin-5-one (AMO) and its seven para- and meta-substituted derivatives (with electron-donating groups R = OH, OCH3, CH3 and electron-withdrawing groups R = Cl, m-Cl, CF3, NO2) were presented by the density functional theory (B3LYP) method. Two types of reaction mechanism, N-path and O-path, are taken into account, in which the attacks by water molecules at the C2 and C5 are accelerated after the protonation on N3 and carbonyl oxygen atoms, respectively. Our computational results clearly manifest that the hydrolysis of AMOs has an obvious substituent effect at the para and meta positions of the benzene ring by correlating the barrier heights with the Hammett constants of substituents. Furthermore, the N-path shows a normal substituent effect, while the favorable O-path shows a reverse substituent effect. The observed reverse substituent effect in experiment actually springs from the reverse substituent effect of the O-path, not the N-path. The substituent effect of the N-path and O-path can be explained by the electrostatic potential at nuclei (EPN) values and Fukui function, respectively. Our theoretical data provided will allow for a better understanding of the acid-promoted hydrolysis mechanism and the observed reverse substituent effect of the AMOs, in nice agreement with the available experimental conclusion.

A new annulated N-heterocyclic carbene (NHC), pyrido[1,2-a]-2-ethyl[1,2,4]triazol-3-ylidene, has been synthesized and its good catalytic activity for benzoin condensation has been experimentally determined by You and co-workers recently [Ma, Y. J., Wei, S. P., Lan, J. B., Wang, J. Z., Xie, R. G., and You, J. S. J. Org. Chem. 2008, 73, 8256]. In this work, the mechanism of the title reaction has been intensively studied computationally by employing the density functional theory (B3LYP) method in conjunction with 6-31+G(d) and 6-311+G(2d,p) basis sets. Our results indicate that path A (in which a sequence of intermolecular proton transfers between two carbene/benzaldehyde coupling intermediates affords enamine) and path B (in which a t-BuOH assisted hydrogen transfer generates enamine) proposed on the basis of the Breslow mechanism are competitive for their similar barriers. In path A, the first intermolecular proton transfer between two N-heterocyclic carbene/benzaldehyde coupled intermediates to form tertiary alcohol and enolate anion is theoretically the rate-determining step with corresponding barrier (30.93 kcal/mol), while the t-BuOH assisted hydrogen transfer generating Breslow enamine is the rate-determining step with corresponding barrier (28.84 kcal/mol) in path B. The coupling of carbene and benzaldehyde, and the coupling of enamine and another benzaldehyde to form a C−C bond are partially rate-determining for their relatively significant barriers (24.06 and 26.95 kcal/mol, respectively), being the same in both paths A and B. Our results are in nice agreement with the experimental result in a kinetic investigation of thiazolium ion-catalyzed benzoin condensation performed by White and Leeper in 2001.

The enzyme aspartate racemase from Pyrococcus horikoshii OT3 catalyzes the interconversion between l- and d-Asp. In this work, we employed the hybrid QM/MM approach with the self-consistent charge-density functional tight binding (SCC-DFTB) model to study the catalytic mechanism for the conversion of l-Asp into d-Asp. The molecular dynamics simulation showed that the substrate l-Asp forms an extensive network of interactions with the active-site residues of the aspartate racemase through its side chain carboxylate, ammonium group, and α-carboxylate. The potential of mean force calculations confirmed that the racemization reaction involves two proton transfers (from the α-carbon to Cys194 and from Cys82 to the α-carbon), which occurs in a concerted way, although highly asynchronous. The calculated free energy of activation is 17.5 kcal/mol, which is consistent with the reaction rate measured from experiment. An electrostatic interaction analysis was performed to estimate the key role played by individual residues in stabilizing the transition state. The docking study on the binding of l-Asp and d-Asp to aspartate racemase indicates that this enzyme employs a “two-base” mechanism not a “one-base” mechanism.

Acetylcholinesterase (AChE) has become an important drug target and its inhibitors have proved useful in the symptomatic treatment of Alzheimer's disease. This work explores several machine learning methods (support vector machine (SVM), k-nearest neighbor (k-NN), and C4.5 decision tree (C4.5 DT)) for predicting AChE inhibitors (AChEIs). A feature selection method is used for improving prediction accuracy and selecting molecular descriptors responsible for distinguishing AChEIs and non-AChEIs. The prediction accuracies are 76.3%∼88.0% for AChEIs and 74.3%∼79.6% for non-AChEIs based on the three kinds of machine learning methods. This work suggests that machine learning methods such as SVM are facilitating for predicting AChEIs potential of unknown sets of compounds and for exhibiting the molecular descriptors associated with AChEIs.Several machine learning methods such as support vector machine, k-nearest neighbor, and C4.5 decision tree were used to predict acetylcholinesterase inhibitors (AChEIs) and non- AChEIs.

Vasodilators have been extensively used in the treatment of various vascular diseases. With the aim of developing the accurate computational models for identifying vasodilators of diverse structures, several machine learning methods, such as C4.5 decision tree (C4.5 DT), k-nearest neighbor (k-NN), and support vector machine (SVM), were explored in this work. These identification models were trained by using 198 three-dimensional molecular descriptors and a group of 635 compounds including 308 vasodilators and 327 non-vasodilators, in which feature selection was conducted to optimize the training models and select the most appropriate descriptors for identifying the vasodilators. An independent validation set of 74 vasodilators and 87 non-vasodilators was subsequently used to evaluate the performance of the developed identification models. The identification rates of these models are in the range of 78.38% –97.30% for vasodilators and 83.91%–86.21% for non-vasodilators. Our investigation reveals that the explored machine learning methods, especially SVM, are potentially useful for the identification of vasodilators.

The reaction mechanism of the cyanide-catalyzed benzoin condensation without protonic solvent assistance has been studied computationally for the first time employing the density functional theory (B3LYP) method in conjunction with 6-31+G(d,p) basis set. Four possible pathways have been investigated. A new proposed pathway on the basis of the Lapworth mechanism is determined to be the dominant pathway in aprotic solvent, in which the formation of the Lapworth’s cyanohydrin intermediate is a sequence including three steps assisted by benzaldehyde, clearly manifesting that the reaction can take place in aprotic solvents such as DMSO. In this favorable pathway with six possible transition states located along the potential energy surface, the reaction of the cyanide/benzaldehyde complex with another benzaldehyde to afford an α-hydroxy ether is the rate-determining dynamically with the activation free energy barrier of 26.9 kcal/mol, and the step to form cyanohydrin intermediate from α-hydroxy ether is partially rate-determining for its relatively significant barrier 20.0 kcal/mol.

The active-site dynamics of human brain aspartoacylase (hASPA) complexed with its substrate (N-acetyl-l-aspartate) has been studied using a hybrid quantum mechanical/molecular mechanical (QM/MM) approach based on the self-consistent charge-density functional tight-binding (SCC-DFTB) model. The Michaelis complex, which is constructed from a recent X-ray structure of the human brain aspartoacylase with a stable tetrahedral intermediate analogue, is reproduced in 1 ns molecular dynamics simulations at 300 K. The simulation shows that the substrate is tightly held in the active site by a hydrogen bond network and the putative nucleophilic water molecule is reasonably close to the nucleophilic center. The catalysis is further modeled with the density functional theory (DFT) in a truncated active-site model at the B3LYP/6-31G(d) level of theory. The DFT calculations indicate the reaction proceeds via a water promoted pathway with Glu178 serving as the general base and general acid. Transition state stabilization for nucleophilic addition is achieved by formations of the weak coordination bond between the substrate carbonyl oxygen atom and the zinc ion as well as of the strong hydrogen bonds between the substrate carbonyl oxygen atom and Arg63.

In this work, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed aminolysis reaction of methyl acetate with methylamine has been investigated at the B3LYP/6-311++G(d,p) and MP2/6-311++G(d,p) levels of theory. In our calculations, we take into account three possible pathways for the reaction. Path 1 is a ‘full concerted’ mechanism via a SN2-like O → N acyl-transfer transition state through the hydrogen bonding of TBD; Path 2 is a stepwise mechanism involving the tetrahedral intermediates through the hydrogen bonding of TBD; and Path 3 is also a stepwise mechanism including the nucleophilic attack of TBD upon ester with covalently bonding of TBD. Results indicate that Path 2 is the likely mechanism and that the hydrogen bonding of TBD has an important role in the aminolysis of ester. The role of the TBD catalyst is to facilitate the proton transfer and accelerate the reaction.

The main primary product of DNA oxidation by free radicals is 5-hydroxy-6- hydroperoxy-5,6-dihydrothymidine (5-OH-6-OOH-DHT), whose further degradation can yield the other mutagenic products and amplify the spectrum of DNA damage. In this study, to illustrate the thermal stability of 5-OH-6-OOH-DHT in DNA, the decomposition mechanism of 5-OH-6-OOH-DHT was identified based on the cis-(5R,6S) diastereomer. Optimized structures for all of the stationary points in the gas phase were investigated at the B3LYP/6-31+G(d,p) level of theory. Four pathways were characterized. The decomposition mechanism of 5-OH-6-OOH-DHT was proposed to involve either dehydration for paths A and B or the cleavage of a glycosidic bond for paths C and D. Moreover, to simulate the title reaction in aqueous solution, a water-mediated mechanism and cluster-continuum model, based on the SCRF/CPCM model, were taken into account. The results indicate that the most favorable reaction pathways for paths A and B both involve a sort of eight-membered ring transition structure formed by two (path A) or one (path B) auxiliary water molecules, suggesting that the thermal decomposition of 5-OH-6-OOH-DHT can be significantly facilitated by water molecules. Path A is the most feasible mechanism reported for the decomposition of 5-OH-6-OOH-DHT in the aqueous solution, which is slightly more favorable than path B. However, the unimolecular decomposition mechanisms (paths C and D) both have high-energy barriers and are largely endothermic, suggesting that the cleavage of the N-glycosidic bond via unimolecular decomposition is thermodynamically and kinetically unfavorable. These studies have shed light on the chemical properties of 5-OH-6-OOH-DHT in free radical reactions and thereby have provided new insights into the complex mechanism of oxidative DNA damage.

The thermodynamic and kinetic properties for the nonenzymatic N-glycosidic bond cleavage in cis-(5R,6S)-5,6-dihydroxy-5,6-dihydrodeoxythymidine (deoxythymidine glycol, dTg) were studied by computational techniques. Optimized structures for all of the stationary points in the gas phase were investigated using the BHandHLYP/6-311++G(d,p) and B3LYP/6-311++G(d,p) methods. Single-point energies were determined employing the ab initio MP2 method in conjunction with the 6-311++G(d,p) basis set. For the unimolecular decomposition of dTg in the gas phase, two pathways were characterized. Subsequently, the hydrolysis of dTg by a single water molecule was investigated. Two possible pathways were considered, involving the abstraction of the C2′ hydrogen followed by the attack of water on the C1′═C2′ bond (SN1 pathway) and the attack of a water molecule on the C1′ atom with the simultaneous cleavage of the glycosidic bond (SN2 pathway). However, both the unimolecular decomposition reaction and the hydrolysis reaction involve large energy barriers, suggesting that the role of water is not beneficial to the overall reaction and the direct involvement of a sole water molecule as a nucleophile is unlikely. This result emphasizes the important catalytic role of enzymes. In addition, the solvent effect of water on the four processes was assessed at the geometry optimization level by means of the conductor-like polarized continuum model. Single-point computation was done at the MP2/6-311++G(d,p)//BHandHLYP/6-311++G(d,p) level. The calculated results show that the presence of the solvent water substantially lowers all energy barriers. Our results give out a greater fundamental understanding of the effects of the nucleophile water and solvent water for this important biological reaction.

The water-assisted hydrolysis mechanism of N,N-dimethyl-N′-(2′,3′-dideoxy-3′-thiacytidine) formamidine (MFA-3TC) with three water molecules was studied by use of computational techniques. Optimized structures for all of the stationary points in the gas phase were investigated using the B3LYP/6-31+G(d,p) method. Single-point energies were determined employing the ab initio MP2 method in conjunction with the 6-311++G(d,p) basis set. Two possible pathways in the title reaction are considered, involving the attack of water molecule at first to the C(1)═N(1) double bond (path A) and the attack of water molecule at first to the C(1)−N(2) single bond (path B), respectively. A local microhydration model concerning three water molecules is adopted to mimic the system for the two reaction mechanisms above, where one water molecule is the nucleophilic reactant and the others are the auxiliary molecules. The calculated results indicate that the first steps in both pathways are the rate-limiting processes, and path A is more favorable than path B in the gas phase. In addition, bulk solvent effect is tested at the geometry optimization level by means of the conductor-like polarized continuum model (CPCM). Single-point computation was done at the MP2/6-311++G(d,p) level based on the geometries in the solution phase. Our results exhibit that the rate-limiting process in both pathways in water is the first step reaction, and path A is still favored. Two pathways are stepwise and slightly endothermic processes.

Computational investigations on the gas-phase nucleophilic substitution reactions of p-substituted phenoxides (p-Y-C6H4O−, Y = OH, CH3O, CH3, H, F, Cl, CF3) with halomethanes (CH3X, X = F, Cl, Br, and I) were performed by the B3LYP and MP2 methods with the 6-311+G(d,p) basis set. Calculated results indicate that the reactions are more endothermic only when the substrate is a lighter halide. The complexation enthalpies, the key parameters in the transition state (TS), the central barriers, overall barriers, overall reaction enthalpies, and the charge of the O4 atom in the TSs all present good correlations with the Hammett constants σ of substituents in the nucleophile. Leffler−Grunwald rate equilibrium relationships predict the degree of bond formation in the transition state suggesting that the reactions have progressed 31%, 24%, 24%, and 21% in the TS for halomethanes (X = F, Cl, Br, and I), respectively. The TS structure with substituents in the nucleophile is not kinetically but thermodynamically controlled, similar to the earlier results. Furthermore, the excellent relationship between the central barrier heights and the looseness of the transition state structure indicates that the stretching of the cleaving bond is one of the major factors determining the central barrier heights. The nucleophilicity of the nucleophile decreases with the increase of the electron-withdrawing power of substituent Y in the nucleophile, while the leaving-group ability of the halogen atom increases with the decrease of its Mulliken electronegativity.

The aminolysis of substituted methylformates (XC(O)OCH3, X = NH2, H, and CF3) in the gas phase and acetonitrile are investigated by the density functional theory B3LYP/6−311+G(d,p) method and Monte Carlo (MC) simulation with free energy perturbation (FEP) techniques. The direct and the ammonia-assisted aminolysis processes are considered, involving the monomeric and dimeric ammonia molecules, respectively. In each case, two different pathways, the concerted and stepwise, are explored. The calculated results show that, for the direct aminolysis, the activation barrier of the concerted path is lower than that of the rate-controlling step of the stepwise process for all three reaction systems. In contrast, for the ammonia-assisted mechanism, the stepwise process is more favorable than the concerted pathway. The substituent effects at the carboxyl C atom of methylformate are discussed. This aminolysis of substituted methylformates is more favored for X = CF3 than for X = H and NH2 in the gas phase for both the direct and the ammonia-assisted processes. Solvent effects of CH3CN on the reaction of HC(O)OCH3 + nNH3 (n = 1, 2) are determined by Monte Carlo simulation. The potential energy profiles along the minimum energy paths in the gas phase and in acetonitrile are obtained. It is shown that CH3CN lowers the energy barriers of all reactions.

The hydrolysis mechanisms of N,N-dimethyl-N′-(2′,3′-dideoxy-3′-thiacytidine)formamidine (FA-3TC) in the gas phase and in aqueous solution were studied by use of the density functional theory B3LYP/6-31+G(d, p) method. Two possible reaction pathways in the title reaction were considered. In one pathway water attacks the C=N double bond first (path A) while in the other water attacks the C-N single bond first (path B). The calculated results indicate that the first step in both pathways is the rate-limiting process and path A is more favorable than path B in the gas phase. The effect of solvent water on the title reaction was assessed at the B3LYP/6-31+G(d, p) level of theory based on the polarizable continuum model (CPCM). In water the first mechanism (path A) is also favored.

This work is an attempt to evaluate the ability of protonation of 8-oxo-2′-deoxyguanosine (8-oxodG) and the effects of oxidation and protonation on its N-glycosidic bond stability by using the density functional theory B3LYP/6-31++G(d, p) method. In all modified forms, the length of the N9–C1′ bond increases as compared to the neutral system 8-oxodG. Especially, the changes are much more obvious for the di-cationic systems. The analysis for the ability of protonation indicates that for the mono-protonated systems, the O8 atom becomes the preferred protonation site in the gas phase. From the dissociation energies of the N-glycosidic bond, it has been found that the homolytic cleavage becomes more difficult upon introducing positive charge in the base ring. In contrast, these systems favor significantly the heterolytic cleavage, especially for the di-cationic systems in which the dissociation energy values are negative. The influence is most prominent with the mono-cation obtained by O8 protonation.

Computational investigations on the enol-to-keto tautomerism of N-methylacetamide (NMA), a simple peptide model, in water are performed by B3LYP and MP2 methods with the 6-311+G(d,p) and 6-311++G(2df,2pd) basis sets. Calculated results indicate that the enol/trans form is less stable than the keto/trans form both in the gas-phase and in water. The effects of solvent water are described using the combined supramolecular/continuum approach based on the SCRF/PCM model, in which one, two, and three water molecules are, respectively, used to assist this tautomerism of NMA. Two possible enol-to-keto tautomeric pathways are considered in this study. The first type of pathway is a stepwise process and characterized by the cis/trans isomerization of the C–N bond. The second type of tautomeric pathway is a concerted mechanism that the hydrogen atom of the enol/trans NMA migrates directly from O to N atom to form the stable keto/trans structure. The results show that the rate-limiting step in the stepwise pathway is the enol/trans-enol/cis isomerization process where the transition state presents a linear conformation approximatively and the reaction energy barrier is little affected by the solvent. In the concerted pathway, at least three water molecules are needed to assist the proton transfer from O to N atom in NMA. It seems that the concerted process with the participation of three water molecules is the most favorable path for the enol-to-keto tautomerism of NMA, because its Gibbs free energy barrier of activation of 11.9 kcal/mol is lower than those of the other pathways.

The acid-promoted hydrolysis of 2,4,4-trimethyloxazolin-5-one (TMO) is studied employing the density functional theory (B3LYP) method in conjunction with the 6−31++G(d,p) basis set. Two types of reaction mechanism, N-protonated and O-protonated, are considered, involving protonation at the nitrogen and carbonyl oxygen of TMO to activate the C2 and C5 atoms, respectively, in favor of attack by water molecules. In the N-protonated pathway, the nucleophilic water molecule attacks the activated C2 atom, with a proton transfer from the water molecule to the oxygen atom attached to C2 and the fission of the C2−O bond, leading to a cis ring-opening product (N-acyl-α-amino isobutyric acid). While, in the O-protonated pathway, the nucleophilic water molecule attacks the activated carbonyl C5 atom, accompanied by a proton transfer from the water molecule toward the nitrogen atom of oxazole ring and the cleavage of C5−O bond; as a result, a corresponding trans product is generated. The water-assisted hydrolysis reactions are also examined together. A local microhydration model, in which an extra water molecule was added to obtain a continuous H-bond network around the reaction centers, was adopted to mimic the system for the two types of reaction processes. In addition, bulk solvent effect is introduced by use of the conductor-like polarizable continuum model (CPCM). Our computational results in kinetics and thermodynamics clearly manifest that the O-protonated pathway with the nucleophilic attack at the carbonyl C5 atom is more favorable than the N-protonated one, in nice agreement with the available experimental conclusion.

The efficient formation of 5-methylcytosine glycol (mCg) and its facile deamination to thymine glycol (Tg) may account for the prevalent C → T transition mutation found at methylated CpG site (mCpG) in human p53 gene, a hallmark for many types of human tumors. In this work, the hydrolytic deamination of mCg was investigated at the MP2 and B3LYP levels of theory using the 6-311G(d,p) basis set. In the gas phase, three pathways were explored, paths A–C, and it indicates that the direct deamination of mCg with H2O by either pathway is unlikely because of the high activation free energies involved in the rate-determining steps, the formation of the tetrahedral intermediate for paths A and B as well as the formation of the Tg tautomer for path C. In aqueous solution, the role of the water molecules in the deamination of mCg with H2O was analyzed in two separate parts: the direct participation of one water molecule in the reaction pathway, called the water-assisted mechanism; and the complementary participation of the aqueous solvation. The water-assisted mechanism was carried out for mCg and the cluster of two water molecules by quantum mechanical calculations in the gas phase. This indicates that the presence of the auxiliary water molecule significantly contributes to decreasing all the activation free energies. The bulk solution effect on the water-assisted mechanism was included by free energy perturbation implemented on Monte Carlo simulations, which is found to be substantial and decisive in the deamination mechanism of mCg. In this case, the water-assisted path A is the most plausible mechanism reported for the deamination of mCg, where the calculated activation free energy (22.6 kcal mol−1 at B3LYP level of theory) agrees well with the experimentally determined activation free energy (24.8 kcal mol−1). The main striking results of the present DFT computational study which is in agreement with previous experimental data is the higher rate of deamination displayed by mCg residues with respect to 5-methylcytosine (mC) bases, which supports that the deamination of mCg contributes significantly to the C → T transition mutation at mCpG dinucleotide site.

An “on water” environment, describing the reactions with insoluble reactants in water, has been reported to give high yields of products compared to organic solvents. The 1,3-dipolar cycloadditions of phthalazinium dicyanomethanide 1 with three different dipolarophiles, methyl vinyl ketone (MVK), methyl acrylate (MAC), and styrene (STY), have been investigated using QM/MM calculations in water, acetonitrile, and acetonitrile–water solvent mixtures, as well as at the vacuum–water interface. Monte Carlo statistical mechanics simulations utilizing the free-energy perturbation theory and PDDG/PM3 for the QM method have been used. The transition structures for all three reactions do not show large variations among different solvents. However, the calculated free energies of activation at the interface are found to be higher than those calculated in bulk water. Computed energy pair distributions and radial distribution functions reveal a uniform loss of hydrogen bonds for the reactants and transitions states in progressing from bulk water to the vacuum–water interface. The hydrophobic effects in the reactions of 1 with MVK and MAC are similar for both, and weaker than the effect in the reaction with STY. According to the results in water–acetonitrile mixtures at different molar ratios, it is clear that the special hydrogen bonding effects are the main reason which leads to the rapid rate enhancement in progressing from a water–acetonitrile molar ratio of 0.9:0.1 to pure water. New insights into solvent effects for 1,3-dipolar cycloadditions are presented herein.