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Ardevol A.,Institute Of Quimica Teorica I Computacional Iqtcub | Biarnes X.,Ramon Llull University | Planas A.,Ramon Llull University | Rovira C.,Institute Of Quimica Teorica I Computacional Iqtcub | Rovira C.,Catalan Institution for Research and Advanced Studies
Journal of the American Chemical Society | Year: 2010

The mechanism of glycosidic bond cleavage by glycosidases involves substrate ring distortions in the Michaelis complex that favor catalysis. Retaining β-mannosidases bind the substrate in a 1S5 conformation, and recent experiments have proposed an unusual substrate conformational pathway (1S5 → B2,5 → OS2) for the hydrolysis reaction. By means of Car-Parrinello metadynamics simulations, we have obtained the conformational free-energy surface (FES) of a β-d-mannopyranose molecule associated with the ideal Stoddart conformational diagram. We have found that 1S 5 is among the most stable conformers and simultaneously is the most preactivated conformation in terms of elongation/shortening of the C1-O1/C1-O5 bonds, C1-O1 orientation, and charge development at the anomeric carbon. Analysis of the computed FES gives support to the proposed 1S 5 → B2,5 → OS2 catalytic itinerary, showing that the degree of preactivation of the substrate in glycoside hydrolases (GHs) is related to the properties of an isolated sugar ring. We introduce a simple preactivation index integrating several structural, electronic, and energetic properties that can be used to predict the conformation of the substrate in the Michaelis complex of any GH. © 2010 American Chemical Society.


Kumar N.,University of Louisville | Alfonso-Prieto M.,Institute Of Quimica Teorica I Computacional Iqtcub | Alfonso-Prieto M.,Temple University | Rovira C.,Institute Of Quimica Teorica I Computacional Iqtcub | And 4 more authors.
Journal of Chemical Theory and Computation | Year: 2011

Quantum chemical computations are used to study the electronic and structural properties of the cob(I)alamin intermediate of the cobalamin-dependent methionine synthase (MetH). QM(DFT)/MM calculations on the methylcobalamin (MeCbl) binding domain of MetH reveal that the transfer of the methyl group to the substrate is associated with the displacement of the histidine axial base (His759). The axial base oscillates between a His-on form in the Me-cob(III)lamin:MetH resting state, where the Co-N(His759) distance is 2.27 Å, and a His-off form in the cob(I)alamin:MetH intermediate (2.78 Å). Furthermore, QM/MM and gas phase DFT calculations based on an unrestricted formalism show that the cob(I)alamin intermediate exhibits a complex electronic structure, intermediate between the Co(I) and Co(II)-radical corrin states. To understand this complexity, the electronic structure of Im⋯[Cob(I)alamin] is investigated using multireference CASSCF/QDPT2 calculations on gas phase models where the axial histidine is modeled by imidazole (Im). It is found that the correlated ground state wave function consists of a closed-shell CoI (d8) configuration and a diradical contribution, which can be described as a CoII (d 7)-radical corrin (π*)1 configuration. Moreover, the contribution of these two configurations depends on the Co-NIm distance. At short Co-NIm distances (<2.5 Å), the dominant electronic configuration is the diradical state, while for longer distances it is the closed-shell state. The implications of this finding are discussed in the context of the methyl transfer reaction between the Me-H4folate substrate and cob(I)alamin. © 2011 American Chemical Society.


Reigada R.,University of Barcelona | Reigada R.,Institute Of Quimica Teorica I Computacional Iqtcub
Journal of Physical Chemistry B | Year: 2011

Molecular dynamics simulations are used to study the influence of chloroform in two different lipid membranes: one representative of a liquid-disordered phase and another one mixed with cholesterol and representative of a liquid-ordered phase. When chloroform is added to the cholesterol-containing membrane, a strong chain disordering is induced. In both cases, chloroform laterally disorganizes the membranes. The analysis of the main structural and dynamical membrane properties reveals that the interaction with cholesterol is the main factor to explain the strong disordering effect of chloroform in liquid-ordered phases. The results support and provide a molecular explanation to the observations of Regen et al. (J. Am. Chem. Soc. 2009, 131, 5068) that suggest that chloroform loosens cholesterol-containing bilayers, thus changing their lateral lipid organization. This lipid-mediated mechanism is conjectured by Regen et al. to be responsible for the anesthetic effect of chloroform and other small volatile anesthetic compounds. This proposal is also discussed. © 2011 American Chemical Society.


Cazorla C.,CSIC - Institute of Materials Science | Rojas-Cervellera V.,Computer Simulation and Modeling Laboratory CoSMoLab | Rojas-Cervellera V.,Institute Of Quimica Teorica I Computacional Iqtcub | Rovira C.,Computer Simulation and Modeling Laboratory CoSMoLab | And 2 more authors.
Journal of Materials Chemistry | Year: 2012

We predict a covalent functionalization strategy for precise immobilization of peptides on carbon nanostructures immersed in water, based on atomistic first-principles simulations. The proposed strategy consists of straightforward decoration of the carbon nanosurfaces (CNS, e.g. graphene and nanotubes) with calcium atoms. This approach presents a series of improvements with respect to customary covalent CNS functionalization techniques: (i) intense and highly selective biomolecule-CNS interactions are accomplished while preserving atomic CNS periodicity, (ii) under ambient conditions calcium-decorated CNS and their interactions with biomolecules remain strongly attractive both in vacuum and aqueous environment, and (iii) calcium coatings already deplete the intrinsic hydrophobicity of CNS thus additional functionalization for CNS water miscibility is not required. The observed biomolecule-CNS binding enhancement can be explained in terms of large electronic transfers from calcium to the oxygen atoms in the carboxyl and side-chain groups of the peptide. The kind of electronic, structural and thermodynamic properties revealed in this work strongly suggest the potential of Ca-decorated CNS for applications in drug delivery and biomaterials engineering. © 2012 The Royal Society of Chemistry.


Vidossich P.,Laboratori Of Simulacio Computacional I Modelitzacio Cosmolab | Vidossich P.,Institute Of Quimica Teorica I Computacional Iqtcub | Alfonso-Prieto M.,Laboratori Of Simulacio Computacional I Modelitzacio Cosmolab | Alfonso-Prieto M.,Institute Of Quimica Teorica I Computacional Iqtcub | And 6 more authors.
Archives of Biochemistry and Biophysics | Year: 2010

The enzymatic cycle of hydroperoxidases involves the resting Fe(III) state of the enzyme and the high-valent iron intermediates Compound I and Compound II. These states might be characterized by X-ray crystallography and the transition pathways between each state can be investigated using atomistic simulations. Here we review our recent work in the modeling of two key steps of the enzymatic reaction of hydroperoxidases: the formation of Cpd I in peroxidase and the reduction of Cpd I in catalase. It will be shown that small conformational motions of distal side residues (His in peroxidases and His/Asn in catalases), not,or only partially, revealed by the available X-ray structures, play an important role in the catalytic processes examined. © 2010 Elsevier Inc.


Vidossich P.,Autonomous University of Barcelona | Alfonso-Prieto M.,Temple University | Rovira C.,Laboratori Of Simulacio Computacional I Modelitzacio Cosmolab | Rovira C.,Institute Of Quimica Teorica I Computacional Iqtcub | Rovira C.,Catalan Institution for Research and Advanced Studies
Journal of Inorganic Biochemistry | Year: 2012

Catalases and peroxidases are ubiquitous heme enzymes that catalyze the removal of hydrogen peroxide (H2O2). Both enzymes use one molecule of hydrogen peroxide to form a high valent iron intermediate named Compound I (Cpd I). However, whereas catalase Cpd I oxidizes a second H 2O2 molecule to oxygen, peroxidases use this intermediate to oxidize other substrates rather than H2O2. The origin of the different reactivity of peroxidases and catalases is not known, but it is likely to be related to structural differences between the two heme active sites. Recent modeling studies suggest that the oxidation of H2O 2 by catalase Cpd I may take place by two hydrogen atom transfer steps. In this work, we investigate how catalases and peroxidases compare along the same hydrogen transfer steps to give hints into the question why peroxidases cannot efficiently oxidize H2O2. The use of simplified models allows us to probe the direct effect of the proximal ligand (tyrosinate in catalases and histidine in peroxidases) without masking from the protein environment. We show that the nature of the fifth ligand (His in peroxidase and Tyr in catalase) has little effect on the energy barriers of the hydrogen transfer steps. On the contrary, the Cpd I-hydrogen peroxide (O Fe-Operoxide) distance affects significantly the reaction barriers. We propose that the distal side architecture of peroxidases do not allow to attain short OCpd I-Operoxide distances, thus resulting in a lower efficiency towards H2O2 oxidation. © 2012 Elsevier Inc. All rights reserved.


Vidossich P.,Laboratori Of Simulacio Computacional I Modelitzacio | Vidossich P.,Institute Of Quimica Teorica I Computacional Iqtcub | Carpena X.,Barcelona Institute for Research in Biomedicine | Loewen P.C.,University of Manitoba | And 2 more authors.
Journal of Physical Chemistry Letters | Year: 2011

By means of quantum mechanics/molecular mechanics calculations, we show that binding of dioxygen to the FeIII enzyme catalase-peroxidase (KatG), responsible for activating the antitubercular drug isoniazid, is possible in the absence of an external reducing agent, thanks to the unique electronic properties of the active site Met-Tyr-Trp adduct. The calculations give support to recent experimental observations suggesting that KatG activates molecular oxygen and suggest that dioxygen activation may be achieved in other enzymes by inserting a residue with low ionization potential near the active site. © 2011 American Chemical Society.


Alfonso-Prieto M.,Temple University | Vidossich P.,Autonomous University of Barcelona | Rovira C.,Institute Of Quimica Teorica I Computacional Iqtcub | Rovira C.,Catalan Institution for Research and Advanced Studies
Archives of Biochemistry and Biophysics | Year: 2012

Catalases are ubiquitous enzymes that prevent cell oxidative damage by degrading hydrogen peroxide to water and oxygen (2H2O2 → 2H2O + O2) with high efficiency. The enzyme is first oxidized to a high-valent iron intermediate, known as Compound I (Cpd I, Por+-FeIV=O) which, at difference from other hydroperoxidases, is reduced back to the resting state by further reacting with H2O2. The normal catalase activity is reduced if Cpd I is consumed in a competing side reaction, forming a species named Cpd I. In recent years, Density Functional Theory (DFT) methods have unraveled the electronic configuration of these high-valent iron species, helping to assign the intermediates trapped in the crystal structures of oxidized catalases. It has been demonstrated that the a priori assumption that the H+/H - type of mechanism for Cpd I reduction leads to the generation of singlet oxygen is not justified. Moreover, it has been shown by ab initio metadynamics simulations that two pathways are operative for Cpd I reduction: a His-mediated mechanism (described as H·/H+ + e-) in which the distal His acts as an acid-base catalyst and a direct mechanism (described as H·/H·) in which the distal His does not play a direct role. Independently of the mechanism, the reaction proceeds by two one-electron transfers rather than one two-electron transfer, as previously assumed. Electron transfer to Cpd I, regardless of whether the electron is exogenous or endogenous, facilitates protonation of the oxoferryl group, to the point that formation of Cpd I may be controlled by the easiness of protonation of reduced Cpd I. © 2012 Elsevier Inc. All rights reserved.


Alfonso-Prieto M.,Computer Simulation and Modeling Laboratory CoSMoLab | Kumar M.,University of Louisville | Rovira C.,Computer Simulation and Modeling Laboratory CoSMoLab | Rovira C.,Institute Of Quimica Teorica I Computacional Iqtcub | And 2 more authors.
Journal of Physical Chemistry B | Year: 2010

The key step in the catalytic cycle of methionine synthase (MetH) is the transfer of a methyl group from the methylcobalamin (MeCbl) cofactor to homocysteine (Hcy). This mechanism has been traditionally viewed as an S N2-type reaction, but a different mechanism based on one-electron reduction of the cofactor (reductive cleavage) has been recently proposed. In this work, we analyze whether this mechanism is plausible from a theoretical point of view. By means of a combination of gas-phase as well as hybrid QM/MM calculations, we show that cleavage of the Co - C bond in a MeCbl· ··Hcy complex (Hcy = methylthiolate substrate (Me-S-), a structural mimic of deprotonated homocysteine) proceeds via a [Co III(corriṅ-)] - Me··· ̇S-Me diradical configuration, involving electron transfer (ET) from a π*corrin-type state to a σ* Co - C one, and the methyl transfer displays an energy barrier ≤8.5 kcal/mol. This value is comparable to the one previously computed for the alternative SN2 reaction pathway (10.5 kcal/mol). However, the ET-based reductive cleavage pathway does not impose specific geometrical and distance constraints with respect to substrate and cofactor, as does the S N2 pathway. This might be advantageous from the enzymatic point of view because in that case, a methyl group can be transferred efficiently at longer distances. © 2010 American Chemical Society.


Ruiz F.X.,Autonomous University of Barcelona | Porte S.,Autonomous University of Barcelona | Gallego O.,Autonomous University of Barcelona | Moro A.,Autonomous University of Barcelona | And 8 more authors.
Biochemical Journal | Year: 2011

Human AKR (aldo-keto reductase) 1C proteins (AKR1C1-AKR1C4) exhibit relevant activity with steroids, regulating hormone signalling at the pre-receptor level. In the present study, investigate the activity of the four human AKR1C enzymes with retinol and retinaldehyde. All of the enzymes except AKR1C2 showed retinaldehyde reductase activity with low Km values (∼1 μM). The kcat values were also low (0.18-0.6 min -1), except for AKR1C3 reduction of 9-cis-retinaldehyde whose k cat was remarkably higher (13 min-1). Structural modelling of the AKR1C complexes with 9-cis-retinaldehyde indicated a distinct conformation of Trp227, caused by changes in residue 226 that may contribute to the activity differences observed. This was partially supported by the kinetics of the AKR1C3 mutant. Retinol/retinaldehyde conversion, combined with the use of the inhibitor flufenamic acid, indicated a relevant role for endogenous AKR1Cs in retinaldehyde reduction in MCF-7 breast cancer cells. Overexpression of AKR1C proteins depleted RA (retinoic acid) transactivation in HeLa cells treated with retinol. Thus AKR1Cs may decrease RA levels in vivo. Finally, by using lithocholic acid as an AKR1C3 inhibitor and UVI2024 as an RA receptor antagonist, we provide evidence that the pro-proliferative action of AKR1C3 in HL-60 cells involves the RA signalling pathway and that this is in part due to the retinaldehyde reductase activity of AKR1C3. © The Authors Journal compilation © 2011 Biochemical Society.

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