Permanently polarized hydroxyapatite for selective electrothermal catalytic conversion of carbon dioxide into ethanol.

Conversion of CO2 into valuable chemicals is not only a very challenging topic but also a socially demanding issue. In this work, permanently polarized hydroxyapatite obtained using a thermal stimulated polarization process is proposed as a highly selective catalyst for green production of ethanol starting from CO2 and CH4.

Biominerals Formed by DNA and Calcium Oxalate or Hydroxyapatite: A Comparative Study.

Biominerals formed by DNA and calcium oxalate (CaOx) or hydroxyapatite (HAp), the most important and stable phase of calcium phosphate) have been examined and compared using a synergistic combination of computer simulation and experimental studies. The interest of this comparison stems from the medical observation that HAp- and CaOx-based microcalcifications are frequently observed in breast cancer tissues, and some of their features are used as part of the diagnosis. Molecular dynamics simulations show that (1) the DNA double helix remains stable when it is adsorbed onto the most stable facet of HAp, whereas it undergoes significant structural distortions when it is adsorbed onto CaOx; (2) DNA acts as a template for the nucleation and growth of HAp but not for the mineralization of CaOx; and (3) the DNA double helix remains stable when it is encapsulated inside HAp nanopores, but it becomes destabilized when the encapsulation occurs into CaOx nanopores. Furthermore, CaOx and HAp minerals containing DNA molecules inside and/or adsorbed on the surface have been prepared in the lab by mixing solutions containing the corresponding ions with fish sperm DNA. Characterization of the formed minerals, which has been focused on the identification of DNA using UV-vis spectroscopy, indicates that the tendency to adsorb and, especially, encapsulate DNA is much smaller for CaOx than for HAp, which is in perfect agreement with results from molecular dynamics simulations. Finally, quantum mechanical calculations have been performed to rationalize these results in terms of molecular interactions, evidencing the high affinity of Ca2+ toward oxalate anions in an aqueous environment.

Diversity at the Water-Metal Interface: Metal, Water Thickness, and Confinement Effects.

The structure and properties of water films in contact with metal surfaces are crucial to understand the chemical and electrochemical processes involved in energy-related technologies. The nature of thin water films on Pd, Pt, and Ru has been investigated by first-principles molecular dynamics to assess how the chemistry at the water-metal surface is responsible for the diversity in the behavior of the water layers closer to the metal. The characteristics of liquid water: the radial distribution functions, coordination, and fragment speciation appear only for unconfined water layers of a minimum of 1.4 nm thick. In addition, the water layer is denser in the region closest to the metal for Pd and Pt, where seven- and five-membered ring motifs appear. These patterns are identical to those identified by scanning tunneling microscopy for isolated water bilayers. On Ru densification at the interface is not observed, water dissociates, and protons and hydroxyl groups are locked at the surface. Therefore, the acid-base properties in the area close to the metal are not perturbed, in agreement with experiments, and the bulk water resembles an electric double layer. Confinement affects water making it closer to ice for both structural and dynamic properties, thus being responsible for the higher viscosity experimentally found at the nanoscale. All these contributions modify the solvation of reactants and products at the water-metal interface and will affect the catalytic and electrocatalytic properties of the surface.

A unified study for water adsorption on metals: meaningful models from structural motifs.

The adsorption of the first water layer on metals combines several structural motifs like pentagons, hexagons, and heptagons interconnected variably leading to a myriad of patterns. Although theoretical methods are now able to discriminate the ground states, there is a need to find simple ways to account for the relative stability of different patterns on the surface. Taking the already reported structures for water bilayers as training sets we have decomposed the adsorption energy of each of the motifs to their fundamental components: water-water and water-metal interactions through strain-induced surface metal deformations. Models coming from this scheme can be used to survey the properties of many of the structures reported irrespectively of their complexity, thus providing a simple structure-based tool to assess the likeliness, relative stability, wettability, and main patterns of water motifs in metals.

Solvent-induced conformational flexibility of a bicyclic proline analogue: Octahydroindole-2-carboxylic acid.

The conformational preferences of the N-acetyl-N'-methylamide derivatives of the four octahydroindole-2-carboxylic acid (Oic) stereoisomers have been investigated in the gas-phase and in aqueous solution using quantum mechanical calculations. In addition to the conformational effects provoked by the stereochemical diversity of Oic, which presents three chiral centers, results provide evidence of interesting and rather unusual features. The conformational preferences of the Oic stereoisomers in solution are only well described by applying a complete and systematic search process, results achieved by simple re-optimization of the gas-phase minima being very imprecise. This is because the conformational rigidity detected in the gas-phase, which is imposed by the chemical restrictions of the fused bicyclic skeleton, disappears in aqueous solution, the four stereoisomers behaving as flexible molecules in this environment. Thus, in general, the γ-turn is the only minimum energy conformation in the gas-phase while in aqueous solution the helical, polyproline-II and γ-turn motifs are energetically favored. Molecular dynamics simulations indicate that the conformational flexibility predicted by quantum mechanical calculations for the four Oic stereoisomers in solution is satisfactorily reproduced by classical force-fields.

Engineering strategy to improve peptide analogs: from structure-based computational design to tumor homing.

We present a chemical strategy to engineer analogs of the tumor-homing peptide CREKA (Cys-Arg-Glu-Lys-Ala), which binds to fibrin and fibrin-associated clotted plasma proteins in tumor vessels (Simberg et al. in Proc Natl Acad Sci USA 104:932-936, 2007) with improved ability to inhibit tumor growth. Computer modeling using a combination of simulated annealing and molecular dynamics were carried out to design targeted replacements aimed at enhancing the stability of the bioactive conformation of CREKA. Because this conformation presents a pocket-like shape with the charged groups of Arg, Glu and Lys pointing outward, non-proteinogenic amino acids α-methyl and N-methyl derivatives of Arg, Glu and Lys were selected, rationally designed and incorporated into CREKA analogs. The stabilization of the bioactive conformation predicted by the modeling for the different CREKA analogs matched the tumor fluorescence results, with tumor accumulation increasing with stabilization. Here we report the modeling, synthetic procedures, and new biological assays used to test the efficacy and utility of the analogs. Combined, our results show how studies based on multi-disciplinary collaboration can converge and lead to useful biomedical advances.

Conformational exploration of two peptides and their hybrid polymer conjugates: potentialities as self-aggregating materials.

In this work we elucidate the conformational preferences of two amyloid-forming peptides, Arginine-Vasopressin and Neuromedin-K, and two new biomacromolecular conjugates obtained by linking the two peptides to a polyester (poly(R-lactic acid)) chain. The conformational properties of the new hybrid conjugates have been assessed through molecular dynamics simulations and compared to those of their individual components. Our results suggest that the free unconjugated peptides tend to adopt backbone arrangements which resemble a ß-hairpin shape, a conformation which has been reported to facilitate amyloid self-aggregation. The backbone conformational preferences of the unlinked peptides are maintained in the peptide-polymer hybrid. Yet significant differences in the side-chains nonbonding interactions patterns were detected between the two states. This suggests that the conformational profile of the peptides' backbones is preserved when linked to the polymer, maintaining the amyloid precursor-like structure. Additionally, several hydrodynamic parameters were computed for both the polylactic acid and for the conjugates: no significant differences were observed, which suggests that the peptide moiety of the hybrid does not significantly affect the conformational tendencies of the polymer chain. Combined, our results provide a conformational exploration of two amyloid-forming peptides and first steps toward the design of two feasible self-aggregating hybrid materials.

Effects of ring contraction on the conformational preferences of α-substituted proline analogs.

The structural consequences derived from the incorporation of either a methyl or a phenyl group at the α carbon of proline were recently investigated by quantum mechanical calculations (J Org Chem 2008, 73, 3418). In this work, the effect produced by contraction of the pyrrolidine ring on such α-substituted proline analogs has been explored using the same computational methods. Specifically, the intrinsic conformational preferences of the N-acetyl-N'-methylamide derivatives of the lower proline homolog L-azetidine-2-carboxylic acid (Aze), characterized by a four- instead of a five-membered ring, and its α-methyl (αMeAze) and α-phenyl (αPhAze) derivatives have been determined using quantum mechanical calculations and compared to those observed before for the proline counterparts. Replacement of the pyrrolidine ring by an azetidine cycle leads to a reduction of the conformational flexibility, especially for the Aze and αMeAze derivatives, which should be attributed to the quasi-planar geometry of the four-membered ring. Furthermore, the azetidine nitrogen shows pyramidalization, which depending on the peptide backbone conformation favors the formation of an attractive N-H···N interaction or alleviates a severe steric hindrance. Calculations on different environments predict that the tendency of αMeAze to adopt γ-turns is higher than that of unsubstituted Aze and α-methylproline, this feature being in full agreement with the experimental observations available.

Integrating the intrinsic conformational preferences of noncoded α-amino acids modified at the peptide bond into the noncoded amino acids database.

Recently, we reported a database (Noncoded Amino acids Database; http://recerca.upc.edu/imem/index.htm) that was built to compile information about the intrinsic conformational preferences of nonproteinogenic residues determined by quantum mechanical calculations, as well as bibliographic information about their synthesis, physical and spectroscopic characterization, the experimentally established conformational propensities, and applications (Revilla-López et al., J Phys Chem B 2010;114:7413-7422). The database initially contained the information available for α-tetrasubstituted α-amino acids. In this work, we extend NCAD to three families of compounds, which can be used to engineer peptides and proteins incorporating modifications at the--NHCO--peptide bond. Such families are: N-substituted α-amino acids, thio-α-amino acids, and diamines and diacids used to build retropeptides. The conformational preferences of these compounds have been analyzed and described based on the information captured in the database. In addition, we provide an example of the utility of the database and of the compounds it compiles in protein and peptide engineering. Specifically, the symmetry of a sequence engineered to stabilize the 3(10)-helix with respect to the α-helix has been broken without perturbing significantly the secondary structure through targeted replacements using the information contained in the database.

Exploring the energy landscape of a molecular engineered analog of a tumor-homing peptide.

Recently a new non-coded amino acid was designed as a replacement for Arg, to protect the tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) from proteases. This constrained Arg analog, denoted c(5)Arg, was engineered to also promote the stability of the CREKA bioactive conformation. The conformational profile of the CREKA analog obtained by replacing Arg by c(5)Arg has been extensively investigated in this work. Two molecular dynamics simulations-based strategies have been employed: a modified simulated annealing and replica exchange. Results obtained using both techniques show that the conformational features of the new analog fulfill the purpose of its design. The new CREKA analog not only preserves the main structural attributes found for the bioactive conformation of the parent peptide but also shows lower flexibility. Moreover, the conformational profile of the mutated peptide narrows towards the most stable structures previously observed for the parent CREKA peptide.

Atomistic modeling of peptides bound to a chemically active surface: conformational implications.

This work presents a computational strategy to model flexible molecules tethered to a metallic rigid surface. The method is based on a previously developed procedure for inert surfaces, in which peptide-surface interactions were not considered. This procedure is able to generate uncorrelated relaxed microstructures at the atomistic level of systems containing relatively high densities of peptides tethered to the surface. The reliability of the strategy has been tested by simulating CREKA (Cys-Arg-Glu-Lys-Ala), a short linear pentapeptide that recognizes clotted plasma proteins and selectively homes to tumors, covalently tethered to a gold surface, results being compared with those obtained when the surface was represented as inert. The results indicate that the whole conformational profile of CREKA presents some correlation with the chemical activity of the surface, even though the bioactive conformation was found as the most favored in all cases. Specifically, simulations reflect that consideration of the peptide-surface interactions affect the geometrical orientation of the side chains, whereas the main chain conformation does not undergo significant modifications.

Key building block of photoresponsive biomimetic systems.

The conformational, electrical, and optical intrinsic properties of L-phenylazophenylalanine (L-PAP), a nonproteinogenic photoresponsive amino acid used to modulate the binding affinity and activity of peptides and proteins, have been systematically investigated using quantum mechanical calculations, with special emphasis being put on the trans-to-cis isomerization of the azobenzene side group. Analyses of the conformational maps and the minimum-energy conformations, which were obtained using density functional theory calculations at the B3LYP/6-311++G(d,p) level, indicate that the semiextended ß is the most favored conformation for both the trans and cis isomers in the gas phase. However, water tends to stabilize the helical backbone arrangement, but only for the cis isomer since this is a sterically forbidden conformation for the trans one. On the other hand, time-dependent density functional theory calculations at the BMK/6-311+G(d,p) level indicate that the peptide backbone does not induce significant changes in the optical properties of the chromophore. This feature was evidenced by both the small dependence of the π→π* and n→π* transition wavelengths with the backbone dihedral angles φ and ψ and the resemblance between the transition wavelengths determined for l-PAP and free azobenzene. In contrast, the dipole moment has been identified as a key property for this photoresponsive amino acid because of its large dependence on both the peptide backbone and the isomerization state.

Conformational preferences of proline analogues with a fused benzene ring.

The intrinsic conformational preferences of indoline-2-carboxylic acid (Inc) and its α-methylated derivative (αMeInc) have been investigated using quantum mechanical calculations. Specifically, the behavior of their N-acetyl-N'-methylamide derivatives, Ac-L-Inc-NHMe and Ac-L-αMeInc-NHMe, has been explored at the B3LYP/6-31+G(d,p) level. Such amino acids are analogues of proline and (α-methyl)proline, respectively, bearing a benzene ring fused to the C(γ)-C(δ) bond of the five-membered pyrrolidine ring. The additional aromatic group has been shown to significantly restrict the conformational space available to these residues by reducing the flexibility of both the five-membered cycle and the peptide backbone. The fused benzene ring also plays a critical role in determining the cis-trans arrangement of the amide bond involving the pyrrolidine nitrogen, which is also modulated by the presence of the α-methyl group in the αMeInc derivative. Furthermore, the influence of the environment on the conformational propensities of these compounds has been evaluated by using both a self-consistent reaction field model and a recently developed interface in a hybrid QM/MM scheme, in which the solvent molecules are treated explicitly with classical mechanics while the solute is described by quantum mechanics at the density functional theory level.

NCAD, a database integrating the intrinsic conformational preferences of non-coded amino acids.

Peptides and proteins find an ever-increasing number of applications in the biomedical and materials engineering fields. The use of non-proteinogenic amino acids endowed with diverse physicochemical and structural features opens the possibility to design proteins and peptides with novel properties and functions. Moreover, non-proteinogenic residues are particularly useful to control the three-dimensional arrangement of peptidic chains, which is a crucial issue for most applications. However, information regarding such amino acids--also called non-coded, non-canonical, or non-standard--is usually scattered among publications specialized in quite diverse fields as well as in patents. Making all these data useful to the scientific community requires new tools and a framework for their assembly and coherent organization. We have successfully compiled, organized, and built a database (NCAD, Non-Coded Amino acids Database) containing information about the intrinsic conformational preferences of non-proteinogenic residues determined by quantum mechanical calculations, as well as bibliographic information about their synthesis, physical and spectroscopic characterization, conformational propensities established experimentally, and applications. The architecture of the database is presented in this work together with the first family of non-coded residues included, namely, alpha-tetrasubstituted alpha-amino acids. Furthermore, the NCAD usefulness is demonstrated through a test-case application example.

Side-chain to backbone interactions dictate the conformational preferences of a cyclopentane arginine analogue.

The intrinsic conformational preferences of the nonproteinogenic amino acids constructed by incorporating the arginine side chain in the beta position of 1-aminocyclopentane-1-carboxylic acid (either in a cis or a trans orientation relative to the amino group) have been investigated by using computational methods. These compounds may be considered as constrained analogues of arginine (denoted as c(5)Arg) in which the orientation of the side chain is fixed by the cyclopentane moiety. Specifically, the N-acetyl-N'-methylamide derivatives of cis- and trans-c(5)Arg have been examined in the gas phase and in solution by using B3LYP/6-311+G(d,p) calculations and Molecular Dynamics simulations. Results indicate that the conformational space available to these compounds is highly restricted, their conformational preferences being dictated by the ability of the guanidinium group in the side chain to establish hydrogen bond interactions with the backbone. A comparison with the behavior previously described for the analogous phenylalanine derivatives is presented.