Biomedical subjects

José M Lluch

Publications and source records attributed to José M Lluch.

At least 19 recordsLinked to original sources

PubMed2007

Kinetic study on the reaction of OH radical with dimethyl sulfide in the absence of oxygen.

A variational transition-state theory calculation for the reaction of OH radical with dimethyl sulfide (DMS) in the absence of oxygen is presented. The potential energy surface was previously studied and the effects of different levels of theory were analyzed. Here we propose a kinetic model for the atmospheric DMS oxidation in the absence of oxygen. For the first time, addition of OH to DMS and CH(3)SOH elimination channels are connected, and the equilibrium approximation in the high-pressure regime is applied to the DMS-OH adduct in the absence of oxygen. Both low- and high-pressure limits are considered to analyze the two different mechanisms of the H-abstraction channel, and two different kinetic approaches are applied to study them. The rate constants for the addition-elimination and H-abstraction routes are compared and the branching ratios are also studied. Tunneling contributions and kinetic isotope effects are analyzed. We conclude, in agreement with experimental observations, that in the absence of oxygen DMS oxidation takes place via H-abstraction with a branching ratio of 1.0 at atmospheric temperatures.

Free Radicals↗

PubMed2007

Methyl vinyl ketone+OH and methacrolein+OH oxidation reactions: a master equation analysis of the pressure- and temperature-dependent rate constants.

High-level electronic structure calculations and master equation analyses were carried out to obtain the pressure- and temperature-dependent rate constants of the methyl vinyl ketone+OH and methacrolein+OH reactions. The balance between the OH addition reactions at the high-pressure limit, the OH addition reactions in the fall-off region, and the pressure-independent hydrogen abstractions involved in these multiwell and multichannel systems, has been shown to be crucial to understand the pressure and temperature dependence of each global reaction. In particular, the fall-off region of the OH addition reactions contributes to the inverse temperature dependence of the rate constants in the Arrhenius plots, leading to pressure-dependent negative activation energies. The pressure dependence of the methyl vinyl ketone+OH reaction is clearly more important than in the case of the methacrolein+OH reaction owing to the weight of the hydrogen abstraction process in this second system. Comparison of the theoretical rate constants and the experimental measurements shows quite good agreement.

Journal Article↗

PubMed2006

A theoretical analysis of rate constants and kinetic isotope effects corresponding to different reactant valleys in lactate dehydrogenase.

In some enzymatic systems large conformational changes are coupled to the chemical step, in such a way that dispersion of rate constants can be observed in single-molecule experiments, each corresponding to the reaction from a different reactant valley. Under this perspective here we present a computational study of pyruvate to lactate transformation catalyzed by lactate dehydrogenase. The reaction consists of a hydride transfer and a proton transfer that seem to take place concertedly. The degree of asynchronicity and the energy barrier depend on the particular starting reactant valley. In order to estimate rate constants we used a free energy perturbation technique adapted to follow the intrinsic reaction coordinate for several possible reaction paths. Tunneling effects are also obtained with a slightly modified version of the ensemble-averaged variational transition state theory with multidimensional tunneling contributions. According to our results the closure of the active site by means of a flexible loop can lead to the formation of different reactant complexes displaying different features in the disposition of some key residues (such as Arg109), interactions with the substrate and number of water molecules in the active site. The chemical step of the reaction takes place with a different reaction rate from each of these complexes. Finally, primary kinetic isotope effects for replacement of the transferring hydrogen of the cofactor with a deuteride are in good agreement with experimental observations, thus validating our methodology.

Catalysis↗

PubMed2006

Enzyme dynamics and tunneling enhanced by compression in the hydrogen abstraction catalyzed by soybean lipoxygenase-1.

A fully microscopical simulation of the rate-limiting hydrogen abstraction catalyzed by soybean lipoxygenase-1 (SLO-1) has been carried out. This enzyme exhibits the largest, and weakly temperature dependent, experimental H/D kinetic isotope effect (KIE) reported for a biological system. The theoretical model used here includes the complete enzyme with a solvation shell of water molecules, the Fe(III)-OH- cofactor, and the linoleic acid substrate. We have used a hybrid QM(PM3/d-SRP)/MM method to describe the potential energy surface of the whole system, and the ensemble-averaged variational transition-state theory with multidimensional tunneling (EA-VTST/MT) to calculate the rate constant and the primary KIE. The computational results show that the compression of the wild-type active site enzyme results in the huge contribution of tunneling (99%) to the rate of the hydrogen abstraction. Importantly, the active site becomes more flexible in the Ile553Ala mutant reactant complex simulation (for which a markedly temperature dependent KIE has been experimentally determined), thus justifying the proposed key role of the gating promoting mode in the reaction catalyzed by SLO-1. Finally, the results indicate that the calculated KIE for the wild-type enzyme has an important dependence on the barrier width.

Binding Sites↗

PubMed2006

Theoretical study on the excited-state intramolecular proton transfer in the aromatic schiff base salicylidene methylamine: an electronic structure and quantum dynamical approach.

The proton-transfer dynamics in the aromatic Schiff base salicylidene methylamine has been theoretically analyzed in the ground and first singlet (pi,pi) excited electronic states by density functional theory calculations and quantum wave-packet dynamics. The potential energies obtained through electronic calculations that use the time-dependent density functional theory formalism, which predict a barrierless excited-state intramolecular proton transfer, are fitted to a reduced three-dimensional potential energy surface. The time evolution in this surface is solved by means of the multiconfiguration time-dependent Hartree algorithm applied to solve the time-dependent Schrödinger equation. It is shown that the excited-state proton transfer occurs within 11 fs for hydrogen and 25 fs for deuterium, so that a large kinetic isotope effect is predicted. These results are compared to those of the only previous theoretical work published on this system [Zgierski, M. Z.; Grabowska, A. J. Chem. Phys. 2000, 113, 7845], reporting a configuration interaction singles barrier of 1.6 kcal mol(-1) and time reactions of 30 and 115 fs for the hydrogen and deuterium transfers, respectively, evaluated with the semiclassical instanton approach.

Journal Article↗

PubMed2006

Potential energy landscape of the photoinduced multiple proton-transfer process in the green fluorescent protein: classical molecular dynamics and multiconfigurational electronic structure calculations.

The green fluorescent protein proton wire operating upon photoexcitation of the internally caged chromophore is investigated by means of classical molecular dynamics and multiconfigurational electronic structure calculations. The structure of the proton wire is studied for the solvated protein, showing that the wire is likely to be found in a configuration ready to operate as soon as the chromophore is photoexcited, and leading to a total of three proton translocations in the vicinity of the chromophore. Multiconfigurational CASSCF and CASPT2 calculations provide a detailed overview of the energy landscape of the proton wire for the ground electronic state S0, the photoactive 1pi pi* state, and the charge-transfer 1pi sigma* state. The results allow discussion of the operation of the wire in terms of the sequence of proton-transfer events and the participation of each electronic state.

Green Fluorescent Proteins↗

PubMed2006

Charge-transfer pipi* excited state in the 7-azaindole dimer. A hybrid configuration interactions singles/time-dependent density functional theory description.

The hybrid configuration interaction singles/time dependent density functional theory approach of Dreuw and Head-Gordon [Dreuw, A.; Head-Gordon, M. J. Am. Chem. Soc. 2004, 126, 4007] has been applied to study the potential energy landscape and accessibility of the charge-transfer pipi* excited state in the dimer of 7-azaindole, which has been traditionally considered a model for DNA base pairing. It is found that the charge-transfer pipi* excited state preferentially stabilizes the product of a single proton transfer. In this situation, the crossing between this state and the photoactive electronic state of the dimer is accessible. It is found that the charge-transfer pipi* excited state has a very steep potential energy profile with respect to any single proton-transfer coordinate and, in contrast, an extremely flat potential energy profile with respect to the stretch of the single proton-transfer complex. This is predicted to bring about a pair of rare fragments of the 7-azaindole dimer, physically separated and hence having very long lifetimes. This could have implications in the DNA base pairs of which the system is an analogue, in the form of replication errors.

Indoles↗

PubMed2006

Variational transition-state theory study of the dimethyl sulfoxide (DMSO) and OH reaction.

The mechanism for the atmospheric oxidation of DMSO has been studied. For the first time, all the possible channels in the DMSO + OH reaction are studied together theoretically, and their corresponding rate constants have been evaluated under the variational transition-state formalism. Three different channels have been characterized: an addition-elimination process to form MSIA (CH3SOOH) and CH3, a H-abstraction pathway to give CH3SOCH2 and H2O, and a nonkinetically relevant S(N)2-type reaction to form methanol and CH3SO. In agreement with previous experimental and theoretical works, the main product in the DMSO + OH reaction turns out to be the MSIA, with a branching ratio at 298.15 K around 97%. The effects of pressure in the global rate constant have also been analyzed.

Journal Article↗

PubMed2006

On the ionization state of the substrate in the active site of glutamate racemase. A QM/MM study about the importance of being zwitterionic.

Computer simulations on a QM/MM potential energy surface have been carried out to gain insights into the catalytic mechanism of glutamate racemase (MurI). Understanding such a mechanism is a challenging task from the chemical point of view because it involves the deprotonation of a low acidic proton by a relatively weak base to give a carbanionic intermediate. First, we have examined the dependency of the kinetics and thermodynamics of the racemization process catalyzed by MurI on the ionization state of the substrate (glutamate) main chain. Second, we have employed an energy decomposition procedure to study the medium effect on the enzyme-substrate electrostatic and polarization interactions along the reaction. Importantly, the present theoretical results quantitatively support the mechanistic proposal by Rios et al. [J. Am. Chem. Soc. 2000, 122, 9373-9385] for the PLP-independent amino acid racemases.

Amino Acid Isomerases↗

PubMed2005

Reaction mechanism of the mandelate anion racemization catalyzed by mandelate racemase enzyme: a QM/MM molecular dynamics free energy study.

The present work studies the reaction mechanism of the racemization of mandelate substrate by mandelate racemase enzyme. The reaction has some intriguing aspects such as the deprotonation of a nonacid hydrogen and the achievement of the pseudosymmetry necessary to obtain the racemic mixture. We will make use of a QM/MM potential energy surface to compute the free energy profiles associated with the reaction. The most favorable reaction mechanism consists of two proton transfers and the configuration inversion of the stereogenic carbon taking place in a concerted manner. We have also designed a suitable reaction coordinate to compute the free energy profiles for this rather complicated reaction. In addition, analysis of the electrostatic effects and bond distances along the reaction will explain how the enzyme accomplishes the catalysis. Finally, the enzymatic reaction will be compared to a model of the uncatalyzed reaction and the catalytic effect of mandelate racemase will be evaluated.

Anions↗

PubMed2005

Elongated dihydrogen versus compressed dihydride complexes: the temperature dependence of the H-D spin-spin coupling constant as a criterion to distinguish between them.

To be able to propose experimental tests to distinguish elongated dihydrogen transition-metal complexes from compressed dihydride transition-metal complexes, a thorough density functional study of the electronic structure in combination with quantum nuclear dynamics calculations have been performed for complexes [Cp*Ru(H2PCH2PCH2(H2)]+ and [CpRe(CO)2H2]. The results of this study suggest that elongated dihydrogen complexes and compressed dihydride complexes have different properties and that it should be possible to distinguish between them experimentally. In particular, different behavior is predicted with respect to 1) the sign of the isotope geometric effect on the H-H distance at 0 K, 2) the temperature dependence of the H-H distance, and 3) the temperature dependence of the H-D spin-spin coupling constant in 1H NMR spectroscopy.

Journal Article↗

PubMed2005

Pressure dependence in the methyl vinyl ketone + OH and methacrolein + OH oxidation reactions: an electronic structure study.

High-level electronic structure calculations were carried out for the study of the reaction pathways in the OH-initiated oxidations of methyl vinyl ketone (MVK) and methacrolein (MACR). For the two conformers of MVK (called synperiplanar and antiperiplanar), the addition channels of OH to the terminal and central carbon atom of the double bond dominate the overall rate constant, whereas the abstraction of the methyl hydrogen atoms has no significant kinetic role. In the case of MACR, only the antiperiplanar conformer is important in its reactivity. In addition, the lower Gibbs free energy barrier for MACR corresponds to the aldehydic hydrogen abstraction reaction, which will be somewhat more favorable than the addition processes. The subtle balance between the different pathways (additions versus abstractions) serves to give an understanding of the pressure dependence of the rate constants of these tropospheric oxidation processes.

Acrolein↗

PubMed2005

Electronic structure study of the initiation routes of the dimethyl sulfide oxidation by OH.

In the present work the potential energy surface (PES) corresponding to the different initiation routes of the oxidation mechanism of DMS by hydroxyl radical in the absence of O(2) has been studied, and connections among the different stationary points have been established. Single-point high level electronic structure calculations at lower level optimized geometries have been shown to be necessary to assure convergence of energy barriers and reaction energies. Our results demonstrate that the oxidation of DMS by OH turns out to be initiated via three channels: a hydrogen abstraction channel that through a saddle point structure finally leads to CH(3)SCH(2) + H(2)O, an addition-elimination channel that firstly leads to an adduct complex (AD) and then via an elimination saddle point structure finally gives CH(3)SOH and CH(3) products, and a third channel that through a concerted pathway leads to CH(3)OH and CH(3)S. The H-abstraction and the addition-elimination channels initiate by a common pathway that goes through the same reactant complex (RC). Our theoretical results agree quite well with the branching ratios experimentally assigned to the formation of the different products. Finally, the calculated equilibrium constants of the formation of the complex AD and the hexadeuterated complex AD from the corresponding reactants, as a function of the temperature, are in good accordance with the experimental values.

Journal Article↗

PubMed2005

Determination of the temperature dependence of the H-D spin-spin coupling constant and the isotope effect on the proton chemical shift for the compressed dihydride complex [CpIr(P-P)H2]2+.

Complex [CpIr(dmpm)H(2)](2+) (dmpm = bis(dimethylphosphino)methane) has been reported to display temperature-dependent spin-spin coupling constant ((1)J(HD)) and isotope effect on the (1)H NMR chemical shift (Deltadelta). A combined electronic structure density functional theory + quantum nuclear dynamics study is used to determine from first-principles the unusual temperature dependence of the spin-spin coupling constant. It is found that the potential energy surface describing the motion of the Ir-H(2) unit has a deeper minimum in the dihydride region and is characterized by important anharmonicities. These anomalies affect the nature of the vibrational states of the unit and are the main reason for the unusual temperature dependence of (1)J(HD) and Deltadelta. These results suggest experimental tests to identify compressed dihydride transition metal complexes.

Journal Article↗

PubMed2005

A fast radical chain mechanism in the polyfluoroalkoxylation of aromatics through NO2 group displacement. Mechanistic and theoretical studies.

Introduction of polyfluoroalkoxy and polyfluoroalkylthio substituents in aromatic rings can be achieved with mild conditions and short times thorough reaction of concentrated solutions of dinitrobenzenes in DMF with polyfluoro alcohols and polyfluoro thiols in moderate excess, in the presence of excess tetrabutylammonium fluoride as a base. Mechanistic studies suggest that under these conditions a fast radical chain mechanism operates. This mechanism is elicited by oxidation of a Meisenheimer complex and proceeds through a radical aromatic substitution with the polyfluoroalkoxy or the polyfluoroalkylthio radicals as key intermediates. At low concentrations, entrainment can be achieved with superoxide anion. A rationale for this effect is discussed. Answers to particular questions about the proposed mechanism are achieved through a theoretical study at the B3LYP/6-31+G(d,p) level. Specifically, the competition between the radical mechanism and the corresponding polar one (classical S(N)Ar reaction) is studied in that way, with the conclusion that the key steps of the radical mechanism in our reaction conditions (polar aprotic solvent) are at least as efficient as the ones of the polar one, thus justifying the observed kinetic advantage for the chain reaction in the conditions where an efficient initiation occurs.

Alcohols↗

PubMed2005

A theoretical study of the competitive homolytic/heterolytic aniomesolytic cleavages of C-O alkyl ether bonds.

Density functional theory electronic structure calculations of the homolytic/heterolytic aniomesolytic C-O fragmentations in the gas phase of a series of radical anions of substituted-phenyl benzyl ethers and substituted-benzyl phenyl ethers have been carried out. Along the series, the electron-withdrawing strength of the substituents increases. An intramolecular electron transfer from the pi system to the sigma molecular orbital of the scissile C-O bond is required to produce the fragmentation. As the electron-withdrawing strength of the substituents increases, the transition-state structures appear later with higher potential energy and Gibbs free energy barriers. The homolytic mesolytic cleavages are always thermodynamically favored versus the corresponding heterolytic mesolytic ones. The heterolytic mesolytic fragmentations in radical anions containing only weak electron-withdrawing groups are faster than the corresponding homolytic mesolytic ones. Conversely, in radical anions supporting strong electron-withdrawing groups the homolytic mesolytic fragmentations are faster in terms of potential energy barriers. However, the entropic contribution makes it comparable the homolytic and the heterolytic Gibbs free energy barriers in this case. The main factors that determine the relative rates of those kind of aniomesolytic cleavages are discussed.

Journal Article↗

PubMed2004

Variational transition state theory as a tool to determine kinetic selectivity in reactions involving a valley-ridge inflection point.

Variational transition state theory has been used to calculate the kinetic isotope effects affecting product ratios in the reaction between (1)O(2) and d(6)-tetramethylethylene. The minimum energy path on the potential energy surface for this process reaches a valley-ridge inflection point and then bifurcates leading to the two final products. Using canonical variational transition state theory, two distinct dynamical bottlenecks were located corresponding to the H- and the D-abstraction, respectively. The calculated KIE at 263 K turns out to be 1.126. Analogously, a H/T KIE of 1.17 at the same temperature has been found for the reaction of (1)O(2) with the tritiated derivative of tetramethylethylene.

Journal Article↗

PubMed2004

Fast hydrogen elimination from the [Ru(PH3)3(CO)(H)2] and [Ru(PH3)4(H)2] complexes in the first singlet excited states: a diabatic quantum dynamics study.

The photodissociation dynamics of [Ru(PH3)3(CO)(H)2] and cis-[Ru(PH3)4(H)2] is theoretically analyzed in the lowest two excited singlet states. Energies obtained through electronic density functional theory calculations that use the time-dependent formalism are fitted to analytical reduced two-dimensional potential energy surfaces (2D-PES). The metal-H2 (R) and H-H (r) distances are the variables of these 2D-PES, the rest of the parameters being kept frozen at the values of the minimum energy structure in the ground electronic state. The time evolution in these 2D-PES is exactly followed by means of a fast Fourier transform algorithm applied to solve the time-dependent Schrödinger equation. A simple diabatization scheme is devised to take into account the probability of transitions between both excited states. The quantum dynamics results point out that photoelimination is almost inexistent if the H2 fragment is to be expelled without further rearrangement of the rest of the complex. Conversely, when the geometries of the complex are optimized by keeping r and R frozen at the hydrogen elimination barrier coordinates, the new 2D-PES so obtained are highly dissociative, the H2 fragment being expelled in less than 100 fs. Finally the picture of the whole reaction that emerges from our theoretical results is described and the main differences between both complexes are examined.

Journal Article↗