A Theoretical Study on the Mechanisms Involved in Catalytic Dehydrogenation and Dehydration of Isopropanol on SrTiO3.

The dehydrogenation and dehydration of isopropanol on the SrO and TiO2 terminated surfaces, of the SrTiO3 perovskite, is addressed by periodic DFT calculations in order to shed light on the involved mechanisms. The results show that the dehydrogenation occurs through a mechanism involving the dissociative adsorption of the alcohol on the SrO terminated surface, followed the nucleophilic attack of a hydride species on the previously adsorbed hydrogen atom to form molecular hydrogen and the corresponding carbonyl compound. The dehydration instead occurs by the molecular adsorption of the alcohol on the TiO2 terminated surface, followed by various possible E1 elimination pathways leading to the formation of the corresponding alkene and a water molecule. The article reports a thorough study on the involved mechanisms, including identification of the transition states and intermediates along the reaction paths, and evaluation of the respective activation barriers, as well. Thus, this article provides significant insights about the mechanisms of dehydrogenation and dehydration of isopropanol on the SrTiO3 , not reported earlier in literature. The calculated barrier energies are in good agreement with experimental values.

A rationale for the unlike potency of avibactam and ETX2514 against OXA-24 ß-lactamase.

Diazabicyclooctanone inhibitors such as ETX2514 and avibactam have shown enhanced inhibitory performance to fight the antibiotic resistance developed by pathogens. However, avibactam is ineffective against Acinetobacter baumannii infections, unlike ETX2514. The molecular basis for this difference has not been tackled from a molecular approach, precluding the knowledge of relevant information. In this article, the mechanisms involved in the inhibition of OXA-24 by ETX2514 and avibactam are studied theoretically by hybrid QM/MM calculations. The results show that both inhibitors share the same inhibition mechanisms, comprising acylation a deacylation stages. The involved mechanisms include the same number of steps, transition states and intermediates; although they differ in the involved activation barriers. This difference accounts for the dissimilar inhibitory ability of both inhibitors. The molecular reason for this is the endocyclic double bond in the piperidine ring of ETX2514 increasing the ring strain and chemical reactivity on the N6 and C7 atoms, besides the methyl substituent, which enhance the hydrophobic character of the ring. Furthermore, Lys218 and the carboxylated Lys84 of ETX2514, play a crucial role in the mechanism by coordinating their protonation states in an on/off (protonated/deprotonated) manner, favoring the proton transference between the residues and the inhibitor.

A theoretical approach for the acylation/deacylation mechanisms of avibactam in the reversible inhibition of KPC-2.

Klebsiella pneumoniae carbapenemase (KPC-2) is the most commonly encountered class A ß-lactamase variant worldwide, which confer high-level resistance to most available antibiotics. In this article we address the issue by a combined approach involving molecular dynamics simulations and hybrid quantum mechanics/molecular mechanics calculations. The study contributes to improve the understanding, at molecular level, of the acylation and deacylation stages of avibactam involved in the inhibition of KPC-2. The results show that both mechanisms, acylation and deacylation, the reaction occur via the formation of a tetrahedral intermediate. The formation of this intermediate corresponds to the rate limiting stage. The activation barriers are 19.5 kcal/mol and 23.0 kcal/mol for the acylation and deacylation stages, respectively. The associated rate constants calculated, using the Eyring equation, are 1.2 × 10-1 and 3.9 × 10-4 (s-1). These values allow estimating a value of 3.3 × 10-3 for the inhibition constant, in good agreement with the experimental value.

Mechanistic study of the biosynthesis of R-phenylacetylcarbinol by acetohydroxyacid synthase enzyme using hybrid quantum mechanics/molecular mechanics simulations.

The biosynthesis of R-phenylacetylcarbinol (R-PAC) by the acetohydroxy acid synthase, (AHAS) is addressed by molecular dynamics simulations (MD), hybrid quantum mechanics/molecular mechanics (QM/MM), and QM/MM free energy calculations. The results show the reaction starts with the nucleophilic attack of the C2α atom of the HEThDP intermediate on the Cß atom of the carbonyl group of benzaldehyde substrate via the formation of a transition state (TS1) with the HEThDP intermediate under 4'-aminopyrimidium (APH+) form. The calculated activation free energy for this step is 17.4 kcal mol-1 at 27 °C. From this point, the reaction continues with the abstraction of Hß atom of the HEThDP intermediate by the Oß atom of benzaldehyde to form the intermediate I. The reaction is completed with the cleavage of the bond C2α-C2 to form the product R-PAC and to regenerate the ylide intermediate under the APH+ form, allowing in this way to reinitiate to the catalytic cycle once more. The calculated activation barrier for this last step is 15.9 kcal mol-1 at 27 °C.

Mechanistic study of the biosynthesis of R-phenylcarbinol by acetohydroxyacid synthase enzyme using hybrid quantum mechanics/molecular mechanics simulations.

The biosynthesis of R-phenylacetylcarbinol (R-PAC) by the acetohydroxy acid synthase, (AHAS) is addressed by molecular dynamics simulations (MD), hybrid quantum mechanics/molecular mechanics (QM/MM), and QM/MM free energy calculations. The results show the reaction starts with the nucleophilic attack of the C2α atom of the HEThDP intermediate on the Cß atom of the carbonyl group of benzaldehyde substrate via the formation of a transition state (TS1) with the HEThDP intermediate under 4'-aminopyrimidium (APH+) form. The calculated activation free energy for this step is 17.4kcal mol-1 at 27 °C. From this point, the reaction continues with the abstraction of Hß atom of the HEThDP intermediate by the Oß atom of benzaldehyde to form the intermediate I. The reaction is completed with the cleavage of the bond C2α-C2 to form the product R-PAC and to regenerate the ylide intermediate under the APH+ form, allowing in this way to reinitiate to the catalytic cycle once more. The calculated activation barrier for this last step is 15.9kcal mol-1 at 27 °C.

Black Trumpet Mushroom-like ZnS incorporated with Cu3P: Noble metal free photocatalyst for superior photocatalytic H2 production.

The development of the efficient photocatalysts with improved photoexcited charge separation and transfer is an essential for the effective photocatalytic H2 generation using light energy. So far, owing to the unique properties and characteristics, the transition metal phosphides (TMPs) have been proven to be high performance co-catalysts to replace some of the classic precious metal materials in the photocatalytic water splitting. In the present work, we report a novel copper phosphide (Cu3P) as a co-catalyst to form a well-designed fabricated photocatalyst with blacktrumpet mushroom-like ZnS semiconductor for the first time. The synthesis of Cu3P/ZnS consists of two-step hydrothermal and ball milling methods. The physical properties of the materials so prepared were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), ultraviolet-visible diffuse reflectance spectroscopy (UV-DRS), X-ray photoelectron spectroscopy (XPS) and Brunauer-Emmett-Teller (BET) analyses. In order to study the role of Cu3P, electrochemical impedance spectroscopy (EIS) measurements were used to investigate the photogenerated charge properties of ZnS. The experiments of photocatalytic production of H2 confirm that the Cu3P co-catalysts effectively promote the separation of photogenerated charge carriers in ZnS, and consequently enhance the H2 evolution activity. The 3% Cu3P/ZnS sample delivers the highest catalyst activity and the consistent H2 evolution rate is14,937 µmol h-1 g-1cat, which is 10-fold boosted compared to the pristine ZnS. The stability of the catalyst was tested by reusing the used 3% Cu3P/ZnS photocatalyst in five consecutive runs, and their respective activity in the H2 production activity was evaluated. A possible mechanism is proposed and discussed.

Molecular Insights on the Release of Avibactam from the Acyl-Enzyme Complex.

Avibactam is a non-ß-lactam ß-lactamase inhibitor for treating complicated urinary tract and respiratory infections caused by multidrug-resistant bacterial pathogens, a serious public health threat. Despite its importance, the release mechanism of avibactam from the enzyme-inhibitor complex has been scarcely studied from first principles, considering the total protein environment. This information at the molecular level is essential for the rational design of new antibiotics and inhibitors. In this article, we addressed the release of avibactam from the complex CTX-M-15 by means of molecular dynamics simulations and quantum mechanics/molecular mechanics calculations. This study provides molecular information not available earlier, including exploration of the potential energy surfaces, characterization of the observed intermediate, and their critical points, as well. Our results show that unlike that observed in the acylation reaction, the residues Glu166 and Lys73 would be in their neutral forms. Release of avibactam follows a stepwise mechanism in which the first stage corresponds to the formation of a tetrahedral intermediate, whereas the second stage corresponds to the cleavage of the Ser70-C7 bond, mediated by Lys73, either directly or through Ser130.

Theoretical Evidence for the Nonoccurrence of Tetrahedral Intermediates in the Deacylation Pathway of the Oxacillinase-24/Avibactam Complex.

Oxacillinases (OXAs) ß-lactamases are of special interest because of their capacity to hydrolyze antibacterial drugs such as cephalosporins and carbapenems, which are frequently used as the last option for the treatment of multidrug-resistant bacteria. Although the comprehension of the involved mechanisms at the atomic level is crucial for the rational design of new inhibitors and antibiotics, currently there is no study on the acylation/deacylation mechanisms of the OXA-24/avibactam complex from first principles; therefore, mechanistic details such as activation barriers, characterization of intermediates, and transition states are still uncertain. In this article, we address the deacylation of the OXA-24/avibactam complex by molecular dynamics simulations and hybrid quantum mechanics/molecular mechanics computations. The study supplies mechanistic details not available so far, namely, topology of the potential energy surfaces, characterization of transition states and intermediates, and calculation of the respective activation barriers. The results show that the deacylation occurs via a mechanism of two stages; the first one involves the formation of a dianionic intermediate with a computed activation barrier of 24 kcal/mol. The second stage corresponds to the cleavage of the OS81-C bond promoted by the protonation of the OS81 atom by the carboxylated Lys84 and the concomitant formation of the C7-N6 bond, allowing the liberation of avibactam and recovery of the enzyme. The calculated activation barrier for the second stage is 13 kcal/mol. The structure of the intermediate, formed in the first stage, does not fulfill the characteristics of a tetrahedral intermediate. These results suggest that the recyclization of avibactam from the OXA-24/avibactam complex may occur without the emergence of tetrahedral intermediates, unlike that observed in the class A CTX-M-15.

Theoretical insights on the inhibition mechanism of a class A Serine Hydrolase by avibactam.

The inhibition mechanism of CTX-M-15 class A serine hydrolase by the inhibitor avibactam is addressed by a combined molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) approach postulating that the residue Ser70 is the sole reacting residue, that is, itself may play the role of the acid-base species required for the enzyme inhibition. Other residues located in the active site have key participation in the positioning of the inhibitor in the right conformation to favor the attack of Ser70, in addition to the stabilization of the transition state by electrostatic interactions with avibactam. The results validate the hypothesis and show that the reaction follows an asynchronous concerted mechanism, in which the nucleophilic attack of the hydroxyl oxygen of Ser70 precedes the protonation of the amidic nitrogen and ring opening. The calculated activation barrier is 16 kcal/mol in agreement with the experimental evidence. © 2018 Wiley Periodicals, Inc.

A QM/MM study on the enzymatic inactivation of cefotaxime.

The reaction between the antibiotic cefotaxime and the CTX-M-14 class A serine hydrolase is addressed from a theoretical point of view, by means of hybrid quantum mechanics/molecular mechanical (QM/MM) calculations, adopting a new approach that postulates that the residue Ser70 itself should play the role of the acid-base species required for the cefotaxime acylation. The proposed mechanism differs from earlier proposals existing in literature for other class A ß-lactamases. The results confirm the hypothesis, and show that the reaction should occur via a concerted mechanism in which the acylation of the lactam carbonyl carbon, protonation of the N7 lactam atom, and opening of the ß-lactam ring occurs simultaneously. Exploration of the potential energy surface shows three critical points, associated with reactants, transition state and product. The transition state is characterized by frequency, intrinsic reaction coordinate, atomic charge, and bond orders calculations. The calculated activation barrier is 20 kcal mol-1, and the reaction appears to be slightly endothermic by about 12 kcal mol-1. We conclude that this approach is feasible, and should be considered as an alternative mechanism or may exist in competition with others already published in the literature. This information should be useful for the design of novel antibiotics and ß-lactamase inhibitors. Graphical abstract Three-dimensional view of the potential energy surface of cefotaxime.

New Insights on the Reaction Pathway Leading to Lactyl-ThDP: A Theoretical Approach.

In all ThDP-dependent enzymes, the catalytic cycle is initiated with the attack of the C2 atom of the ylide intermediate on the Cα atom of a pyruvate molecule to form the lactyl-ThDP (L-ThDP) intermediate. In this study, the reaction between the ylide intermediate and pyruvate leading to the formation of L-ThDP is addressed from a theoretical point of view. The study includes molecular dynamics, exploration of the potential energy surface by means of QM/MM calculations, and reactivity analysis on key centers. The results show that the reaction occurs via a concerted mechanism in which the carboligation and the proton transfers occur synchronically. It is also observed that during the reaction the protonation state of the N1' atom changes: the reaction starts with the ylide having the N1' atom deprotonated and reaches a transition state showing the N1' atom protonated. This conversion leads to the reaction path of minimum energy, with an activation energy of about 20 kcal mol(-1). On the other hand, it is also observed that the approaching distance between the pyruvate and the ylide, i.e., the Cα-C2 distance, plays a fundamental role in the reaction mechanism since it determines the nucleophilic character of key atoms of the ylide, which in turn trigger the elemental reactions of the mechanism.

How important is the synclinal conformation of sulfonylureas to explain the inhibition of AHAS: a theoretical study.

The inhibitory activity of 15 sulfonylureas on acetohydroxyacid synthase (AHAS) is addressed theoretically in order to stress how important the conformation is to explain their differences as AHAS inhibitors. The study includes calculations in gas phase, solution, and in the enzymatic environment. The results suggest that both the activation Gibbs free energy and Gibbs free energy change associated with the conformational change in solution allow for determining if sulfonylureas should have high or low inhibition activity. QM/MM calculations were also carried out in order to identify the role of the amino acid residues and the effects involved in the stabilization of the active conformation in the binding pocket. On the other hand, the analysis of the frontier molecular orbitals of the sulfonylureas in the binding pocket allowed us to explain the inhibitory activity in terms of the reactivity of the carbonyl carbon.

A QM/MM study on the reaction pathway leading to 2-aceto-2-hydroxybutyrate in the catalytic cycle of AHAS.

The reaction between the intermediate 2-hydroxyethyl-thiamin diphosphate (HEThDP(-) ) and 2-ketobutyrate, in the third step of the catalytic cycle of acetodydroxy acid synthase, is addressed from a theoretical point of view by means of hybrid quantum/molecular mechanical calculations. The QM region includes one molecule of 2-ketobutyrate, the HEThDP(-) intermediate, and the residues Arg 380 y Glu 139; whereas the MM region includes the rest of the protein. The study includes potential energy surface scans to identify and characterize critical points on it, transition state search and activation barrier calculations. The results show that the reaction occurs via a two-step mechanism corresponding to the carboligation and proton transfer in the first stage; and the product release in the second step.

Electron density reactivity indexes of the tautomeric/ionization forms of thiamin diphosphate.

The generation of the highly reactive ylide in thiamin diphosphate catalysis is analyzed in terms of the nucleophilicity of key atoms, by means of density functional calculations at X3LYP/6-31++G(d,p) level of theory. The Fukui functions of all tautomeric/ionization forms are calculated in order to assess their reactivity. The results allow to conclude that the highly conserved glutamic residue does not protonate the N1' atom of the pyrimidyl ring, but it participates in a strong hydrogen bonding, stabilizing the eventual negative charge on the nitrogen, in all forms involved in the ylide generation. This condition provides the necessary reactivity on key atoms, N4' and C2, to carry out the formation of the ylide required to initiate the catalytic cycle of ThDP-dependent enzymes. This study represents a new approach for the ylide formation in ThDP catalysis.

Computer-assisted study on the reaction between pyruvate and ylide in the pathway leading to lactyl-ThDP.

In this study the formation of the lactyl-thiamin diphosphate intermediate (L-ThDP) is addressed using density functional theory calculations at X3LYP/6-31++G(d,p) level of theory. The study includes potential energy surface scans, transition state search, and intrinsic reaction coordinate calculations. Reactivity is analyzed in terms of Fukui functions. The results allow to conclude that the reaction leading to the formation of L-ThDP occurs via a concerted mechanism, and during the nucleophilic attack on the pyruvate molecule, the ylide is in its AP form. The calculated activation barrier for the reaction is 19.2 kcal/mol, in agreement with the experimental reported value.

Density-functional study on the equilibria in the ThDP activation.

The equilibria among the various ionization and tautomeric states involved in the activation of ThDP is addressed using high level density functional theory calculations, X3LYP/6-311++G(d,p)//X3LYP(PB)/6-31++G(d,p). This study provides the first theoretically derived thermodynamic data for the internal equilibria in the activation of ThDP. The role of the medium polarity on the geometry and thermodynamics of the diverse equilibria of ThDP is addressed. The media chosen are cyclohexane and water, as paradigms of apolar and polar media. The results suggest that all ionization and tautomeric states are accessible during the catalytic cycle, even in the absence of substrate, being APH(+) the form required to interconvert the AP and IP tautomers; and the generation of the ylide proceeds via the formation of the IP form. Additionally, the calculated ΔG° values allow to calculate all the equilibrium constants, including the pK(C2) for the thiazolium C2 atom whose ionization is believed to initiate the catalytic cycle.

Theoretical calculation of partition coefficients of dimethoxypyrimidinylsalicylic acids.

Despite their importance as herbicides, dimethoxypyrimidinylsalicylic acids has been poorly characterized from a physical-chemical point of view. This lack of information has prevented the assessment of their impact in the environment once they are released. In this study, environmentally important properties (free energy of solvation, Henry's law constant, octanol/air, and octanol/water partition coefficients) of 39 dimethoxypyrimidinylsalicylic derived compounds are calculated by density functional theory (DFT) methods at B3LYP/6-31G(d,p) level of theory using the Poisson-Boltzmann solvation model. These properties have not been reported previously for this family of compounds, neither experimentally or theoretically.

Quantitative prediction of solvation free energy in octanol of organic compounds.

The free energy of solvation, DeltaGS0, in octanol of organic compounds is quantitatively predicted from the molecular structure. The model, involving only three molecular descriptors, is obtained by multiple linear regression analysis from a data set of 147 compounds containing diverse organic functions, namely, halogenated and non-halogenated alkanes, alkenes, alkynes, aromatics, alcohols, aldehydes, ketones, amines, ethers and esters; covering a DeltaGS0 range from about -50 to 0 kJ.mol(-1). The model predicts the free energy of solvation with a squared correlation coefficient of 0.93 and a standard deviation, 2.4 kJ.mol(-1), just marginally larger than the generally accepted value of experimental uncertainty. The involved molecular descriptors have definite physical meaning corresponding to the different intermolecular interactions occurring in the bulk liquid phase. The model is validated with an external set of 36 compounds not included in the training set.

Predicting infinite dilution activity coefficients of organic compounds in water by quantum-connectivity descriptors.

Quantitative structure-property relationship (QSPR) models are developed to predict the logarithm of infinite dilution activity coefficient of hydrocarbons, oxygen containing organic compounds and halogenated hydrocarbons in water at 298.15 K. The description of the molecular structure in terms of quantum-connectivity descriptors allows to obtain more simple QSPR models because of the quantum-chemical and topological information coded in this type of descriptors. The models developed in this paper have fewer descriptors and better statistics than other models reported in literature. The current models allow a more transparent physical interpretation of the phenomenon in terms of intermolecular interactions which occur in solution and which explain the respective deviations from ideality.

Quantum-connectivity descriptors in modeling solubility of environmentally important organic compounds.

Quantum-connectivity indices are topographic descriptors combining quantum-chemical and topological information. They are used to describe the water solubility of a noncongeneric data set of organic compounds. A QSPR model is obtained with two quantum-connectivity indices that accounts for more than 90% of the variance in the water solubility of these chemicals. This model is compared to other five QSPR models using constitutional, electrostatic, geometric, quantum-chemical, and topological descriptors calculated by CODESSA. None of these models accounts for more than 85% of the variance in water solubility of the compounds in this data set. The QSPR model obtained with quantum-connectivity indices is also better than that generated from the general pool of 508 CODESSA indices. Models with up to five variables were explored and compared with the model obtained here. It is shown that quantum-connectivity indices contain more structural information than other classes of descriptors at least for describing the water solubility of these 53 chemicals. Structural interpretation of the QSPR model developed as well as the role of the quantum-connectivity indices included in it are also analyzed.