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Ardevol A.,Computer Simulation and Modeling Laboratory CosMoLab | Rovira C.,Computer Simulation and Modeling Laboratory CosMoLab | Rovira C.,Catalan Institution for Research and Advanced Studies
Angewandte Chemie - International Edition | Year: 2011

A quantum leap: By means of quantum mechanics/molecular mechanics metadynamics simulations, a front-face SNi-type reaction for glycosyl transfer with retention of the anomeric configuration is shown to be feasible. A short-lived oxocarbenium-like species (see picture; O red, P gold, N blue, C black) is identified and provides the complete itinerary of this long sought after molecular mechanism. © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Petersen L.,Iowa State University | Ardevol A.,Computer Simulation and Modeling Laboratory CosMoLab | Ardevol A.,University of Barcelona | Rovira C.,Computer Simulation and Modeling Laboratory CosMoLab | And 3 more authors.
Journal of the American Chemical Society | Year: 2010

Golgi α-mannosidase II (GMII), a member of glycoside hydrolase family 38, cleaves two mannosyl residues from GlcNAcMan5GlcNAc2 as part of the N-linked glycosylation pathway. To elucidate the molecular and electronic details of the reaction mechanism, in particular the conformation of the substrate at the transition state, we performed quantum mechanics/molecular mechanics metadynamics simulations of the glycosylation reaction catalyzed by GMII. The calculated free energy of activation for mannosyl glycosylation (23 kcal/mol) agrees very well with experiments, as does the conformation of the glycon mannosyl ring in the product of the glycosylation reaction (the covalent intermediate). In addition, we provide insight into the electronic aspects of the molecular mechanism that were not previously available. We show that the substrate adopts an OS2/B2,5 conformation in the GMII Michaelis complex and that the nucleophilic attack occurs before complete departure of the leaving group, consistent with a DNA N reaction mechanism. The transition state has a clear oxacarbenium ion (OCI) character, with the glycosylation reaction following an OS2/B2,5 a B2,5 [TS] a 1S5 itinerary, agreeing with an earlier proposal based on comparing α- and β-mannanases. The simulations also demonstrate that an active-site Zn ion helps to lengthen the O2′-HO2′ bond when the substrate acquires OCI character, relieving the electron deficiency of the OCI-like species. Our results can be used to explain the potency of recently formulated GMII anticancer inhibitors, and they are potentially relevant in deriving new inhibitors. © 2010 American Chemical Society. Source


Nygaard T.P.,Technical University of Denmark | Alfonso-Prieto M.,Computer Simulation and Modeling Laboratory CosMoLab | Alfonso-Prieto M.,Roskilde University | Peters G.H.,Technical University of Denmark | And 5 more authors.
Journal of Physical Chemistry B | Year: 2010

Although the Escherichia coli ammonia transporter B (AmtB) protein has been the focus of several recent studies, there are still many questions and controversies regarding substrate binding and recognition. Specifically, how and where AmtB differentiates between substrates is not yet fully understood. The present computational study addresses the importance of intermolecular interactions with respect to substrate recruitment and recognition by means of ab initio QM/MM simulations. On the basis of calculations with substrates NH3, NH4 +, Na+, and K+ positioned at the periplasmic binding site (Am1) and NH3 and NH 4 + at intraluminal binding sites (Am1a/b), we conclude that D160 is the single most important residue for substrate recruitment, whereas cation-π interactions to W148 and F107 are found to be less important. Regarding substrate recruitment and recognition, we find that only NH4 + and K+ reach the Am1 site. However, NH4 + has the largest affinity for this site due to its better dehydration compensation, while charge stabilization effects favor the binding of NH4 + over NH3 (i.e., if NH 3 would enter the Am1 site, it is likely to be protonated). Therefore, we conclude that the Am1 site selects NH4 + over Na+, K+ and NH3. Our calculations also suggest that translocation of NH4 + from Am1 into the channel lumen is driven by rotation of the A162-G163 peptide bond, which coordinates NH4 + but not NH3 at both Am1 and Am1a/b sites. © 2010 American Chemical Society. Source


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. Source


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. Source

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