Doped photo-crosslinked polyesteramide hydrogels as solid electrolytes for supercapacitors.

High-performance hydrogels play a crucial role as solid electrolytes for flexible electrochemical supercapacitors (ESCs). More specifically, all solid-state ESCs based on renewable, biodegradable and/or biocompatible hydrogels doped with inorganic salts as electrolytes are attractive not only because of their contribution to reducing resource consumption and/or the generation of electronic garbage, but also due to their potential applicability in the biomedical field. Here, computer simulations have been combined with experimental measurements to probe the outstanding capability as solid electrolytes of photo-crosslinked unsaturated polyesteramide hydrogels containing phenylalanine, butenediol and fumarate, and doped with NaCl (UPEA-Phe/NaCl). Atomistic molecular dynamics simulations have shown the influence of the hydrogel pore structure in the migration of Na+ and Cl- ions, suggesting that UPEA-Phe/NaCl hydrogels prepared without completing the photo-crosslinking reaction will exhibit better behavior as solid electrolytes. Theoretical predictions have been confirmed by potentiodynamic and galvanostatic studies on ESCs fabricated using poly(3,4-ethylenedioxythiophene) electrodes and UPEA-Phe/NaCl hydrogels, which were obtained using different times of exposure to UV radiation (i.e. 4 and 8 h for incomplete and complete photo-crosslinking reaction). Moreover, the behavior as a solid electrolyte of the UPEA-Phe/NaCl hydrogel prepared using a photo-polymerization time of 4 h has been found to be significantly superior to those exhibited by different polypeptide and polysaccharide hydrogels, which were analyzed using ESCs with identical electrodes and experimental conditions.

An atomic finite element model for biodegradable polymers. Part 1. Formulation of the finite elements.

Molecular dynamics (MD) simulations are widely used to analyse materials at the atomic scale. However, MD has high computational demands, which may inhibit its use for simulations of structures involving large numbers of atoms such as amorphous polymer structures. An atomic-scale finite element method (AFEM) is presented in this study with significantly lower computational demands than MD. Due to the reduced computational demands, AFEM is suitable for the analysis of Young's modulus of amorphous polymer structures. This is of particular interest when studying the degradation of bioresorbable polymers, which is the topic of an accompanying paper. AFEM is derived from the inter-atomic potential energy functions of an MD force field. The nonlinear MD functions were adapted to enable static linear analysis. Finite element formulations were derived to represent interatomic potential energy functions between two, three and four atoms. Validation of the AFEM was conducted through its application to atomic structures for crystalline and amorphous poly(lactide).

Atomistic simulations of the structure of highly crosslinked sulfonated poly(styrene-co-divinylbenzene) ion exchange resins.

The microscopic structures of highly crosslinked sulfonated poly(styrene-co-divinylbenzene) resins have been modeled by generating atomistic microstructures using stochastic-like algorithms, which are subsequently relaxed using molecular dynamics. Two different generation algorithms have been tested. The relaxation of the microstructures generated by the first algorithm, which is based on a homogeneous construction of the resin, leads to a significant overestimation of the experimental density as well as to an unsatisfactory description of the porosity. In contrast, the generation approach that combines algorithms for the heterogeneous growing and branching of the chains enables the formation of crosslinks with different topologies. In particular, the intrinsic heterogeneity observed in these resins is efficiently reproduced when the topological loops, which are defined by two or more crosslinks closing a cycle, are present in their microscopic description. Thus, the apparent density, porosity and pore volume estimated using microstructures with these topological loops, called super-crosslinks, are in very good agreement with the experimental results. Although the backbone dihedral angle distribution of the generated and relaxed models is not influenced by the topology, the number and type of crosslinks affect the medium- and long-range atomic disposition of the backbone atoms and the distribution of sulfonic groups. An analysis of the distribution of the local density indicates that super-crosslinks are responsible for the heterogeneous homogenization observed during the MD relaxation. Finally the π-π stacking interactions have been analyzed. Results indicate that those in which the two rings adopt a T-shaped disposition are considerably more abundant as compared to those with the co-facially oriented rings, independently of the resin topology.

Atomistic organization and characterization of tube-like assemblies comprising peptide-polymer conjugates: computer simulation studies.

The structure and stability of the nanotube obtained by assembling peptide-polymer conjugates consisting of two poly(n-butyl acrylate) blocks coupled to the cyclic (D-alt-L)-octapeptide cyc[(L-Gln-D-Ala-L-Lys-D-Ala)2], have been investigated at the molecular level using atomistic molecular dynamics simulations. The effect of the wrapping polymer shells in the tube-like core, which consists of stacked beta-sheet cyclopeptides, has been examined by simulating assemblies of both unsubstituted cyclopeptides, and conjugates in chloroform and N,N-dimethylformamide solutions. Furthermore, the influence of the environment has been investigated by comparing conjugate assemblies in solution with those deposited on mica. In addition, nanotubes stabilized by beta-sheet-like hydrogen bonds between both parallel and antiparallel oriented cyclopeptides have been considered in all cases. The results, which have been analysed in terms of energy contributions, partial radial distribution functions, inter-subunit distances, shape of the cyclopeptide ring, internal van der Waals diameters, and both height and width of the nanostructures deposited on mica, have provided important microscopic insights. For example, analysis of both the energy terms and the structural dynamics obtained for the different assemblies indicate that the mica surface interacts more favourably with the parallel assembly than with the antiparallel ones, whereas the only configuration that is structurally stable in solution is the latter. Furthermore, adsorption onto the solid substrate produces a small deformation of the cylindrical molecular system.

Stochastic simulation of structural properties of natively unfolded and denatured proteins.

A new simulation strategy based on a stochastic process has been developed and tested to study the structural properties of the unfolded state of proteins at the atomistic level. The procedure combines a generation algorithm to produce representative uncorrelated atomistic microstructures and an original relaxation method to minimize repulsive non-bonded interactions. Using this methodology, a set of 14 unfolded proteins, including seven natively unfolded proteins as well as seven "classical" proteins experimentally described in denaturation conditions, has been investigated. Comparisons between the calculated and available experimental values of several properties, at hydrodynamic and atomic level, used to describe the unfolded state, such as the radius of gyration, the maximum length, the hydrodynamic radius, the diffusion coefficient, the sedimentation coefficient, and the NMR chemical shifts, reflect a very good agreement. Furthermore, our results indicate that the relationship between the radius of gyration and the hydrodynamic radius deviates from the Zimm's theory of polymer dynamics for random coils, as was recently observed using single-molecule fluorescent methods. Simulations reveal that the interactions between atoms separated by three chemical bonds (1-4 interactions) play a crucial role in the generation process, suggesting that the unfolded state is essentially governed by bonding and short-range non-bonding interactions.

Hexaazatriphenylene (HAT) versus tri-HAT: the bigger the better?

A new hexaazatriphenylene (HAT) derivative formed by the fusion of three HAT units has been prepared and its electronic and molecular structures have been fully characterized by optical and vibrational Raman spectroscopy, electrochemistry, solid-state UV and inverse photoemission spectroscopy (UPS and IPES), and by quantum-chemical calculations. A comparative HAT versus tri-HAT study was performed. The fusion of three HAT molecules causes modifications in the optical and electrochemical properties consistent with enhanced π-electron delocalization attained in a bigger planar core. Such combined experimental and theoretical studies are useful to balance chemical design with supramolecular engineering directed to find enhanced characteristics for new organic semiconductor applications.

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.

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.

A simulation strategy for the atomistic modeling of flexible molecules covalently tethered to rigid surfaces: application to peptides.

A computational strategy to model flexible molecules tethered to a rigid inert surface is presented. The strategy is able to provide uncorrelated relaxed microstructures at the atomistic level. It combines an algorithm to generate molecules tethered to the surface without atomic overlaps, a method to insert solvent molecules and ions in the simulation box, and a powerful relaxation procedure. The reliability of the strategy has been investigated by simulating two different systems: (i) mixed monolayers consisting of binary mixtures of long-chain alkyl thiols of different lengths adsorbed on a rigid inert surface and (ii) CREKA (Cys-Arg-Glu-Lys-Ala), a short linear pentapeptide that recognizes clotted plasma proteins and selectively homes to tumors, covalently tethered to a rigid inert surface in aqueous solution. In the first, we examined the segregation of the two species in the monolayers using different long-chain:short-chain ratios, whereas in the second, we explored the conformational space of CREKA and ions distribution considering densities of peptides per nm(2) ranging from 0.03 to 1.67. Results indicate a spontaneous segregation in alkyl thiol monolayers, which enhances when the concentration of longest chains increases. However, the whole conformational profile of CREKA depends on the number of molecules tethered to the surface pointing out the large influence of molecular density on the intermolecular interactions, even though the bioactive conformation was found as the most stable in all cases.

Modeling of amorphous polyaniline emeraldine base.

Amorphous polyaniline emeraldine base has been investigated using atomistic classical molecular dynamics simulations. Initially, different sets of force-field parameters, which differ in the atomic charges and/or the van der Waals parameters, were tested. The experimental density of polyaniline was satisfactorily reproduced using the following combination: (i) equilibrium bond lengths, equilibrium bond angles, and electrostatic charges derived from quantum mechanical calculations and (ii) van der Waals parameters extrapolated from GROMOS for all atoms with the exception of the CH pseudoparticles of the phenyl ring, which were taken from an anisotropic united atom potential. Next, this force field was used to investigate the structure of the polymer in the amorphous state, the trajectories performed for this purpose allowing accumulation of 750 ns. Analyses of the energies evidence that the interactions between one repeating unit containing an amine nitrogen atom and another unit with an imine nitrogen are favored with respect to those between two identical repeating units. This conclusion is also supported by quantum mechanical and quantum mechanical/molecular mechanics calculations. On the other hand, the partial radial distribution functions indicate that this material only exhibits short-range intramolecular correlation, which is in excellent agreement with experimental evidence.

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.

Influence of the dye presence on the conformational preferences of CREKA, a tumor homing linear pentapeptide.

The conformational properties of the Cys-Arg-Glu-Lys-Ala (CREKA) peptide sequence labeled with fluorescein, a fluorescent dye attached to the Cys through a flexible linker have been examined using molecular dynamics simulations. The CREKA sequence has been identified as a tumor-homing peptide that effectively binds to clotted plasma proteins. Before conformational exploration, the molecular geometry, basicity and spectroscopic properties of this dye, which is essential for the imaging the peptide activity, have been examined using quantum mechanical calculations, with the results also allowing determination of the force-field parameters required for classical simulations. Minimum energy conformations derived from the conformational search have been classified using clustering analyses with criteria based on both the existence of interactions and backbone geometric similarity. The results have been compared with those reported for isolated CREKA (peptide without dye). We found that the fluorescein affects the energy distribution of the minimum energy conformations, with the repulsive steric interactions induced by the dye producing shifting the distribution towards higher energy values. Interestingly, although the structural characteristics of the bioactive conformation identified for CREKA are not perturbed by the dye, it is less stable when the peptide is attached to the dye than in other chemical environments previously studied (isolated peptide, peptide attached to the surface of a protein, and peptide inserted in a phage display protein).

The energy landscape of a selective tumor-homing pentapeptide.

Recently, a potentially powerful strategy based on phage-display libraries has been presented to target tumors via homing peptides attached to nanoparticles. The Cys-Arg-Glu-Lys-Ala (CREKA) peptide sequence has been identified as a tumor-homing peptide that binds to clotted plasmas proteins present in tumor vessels and interstitium. The aim of this work consists of mapping the conformational profile of CREKA to identify the bioactive conformation. For this purpose, a conformational search procedure based on modified simulated annealing combined with molecular dynamics was applied to three systems that mimic the experimentally used conditions: (i) the free peptide; (ii) the peptide attached to a nanoparticle; and (iii) the peptide inserted in a phage display protein. In addition, the free peptide was simulated in an ionized aqueous solution environment, which mimics the ionic strength of the physiological medium. Accessible minima of all simulated systems reveal a multiple interaction pattern involving the ionized side chains of Arg, Glu, and Lys, which induces a beta-turn motif in the backbone observed in all simulated CREKA systems.

Coarse-graining the self-assembly of beta-helical protein building blocks.

Nanotubular structures constructed using self-assembled beta-helical protein building blocks one atop the other have been coarsened to develop a mesoscopic potential that reproduces the intermolecular interaction energies provided by atomistic force-fields. The resulting potential consists of an analytical expression that depends exclusively on the distance and the relative orientation between the two interacting entities. In spite of its complexity, this coarse-grained potential reproduces satisfactorily the energetic properties of two interacting building blocks. The coarse-grained potential has been used to predict that the interaction between building blocks formed by residues 131-165 of E. coli galactoside acteyltransferase becomes repulsive when the size of the nanotube is larger than a threshold, that is, about 45 self-assembled building blocks.

Coarse-grained representation of beta-helical protein building blocks.

A general strategy to develop coarse-grained models of beta-helical protein fragments is presented. The procedure has been applied to a building block formed by a two-turn repeat motif from E. coli galactoside acetyltransferase, which is able to provide a very stable self-assembled tubular nanoconstruct upon stacking of its replicas. For this purpose, first, we have developed a computational scheme to sample very efficiently the configurational space of the building block. This method, which is inspired by a strategy recently designed to study amorphous polymers and by an advanced Monte Carlo algorithm, provides a large ensemble of uncorrelated configurations at a very reasonable computational cost. The atomistic configurations provided by this method have been used to obtain a coarse-grained model that describes the amino acids with fewer particles than those required for full atomistic detail, i.e., two, three, or four depending on the chemical nature of the amino acid. Coarse-grained potentials have been developed considering the following types of interactions: (i) electrostatic and van der Waals interactions between residues i and i + n with n >/= 2; (ii) interactions between residues i and i + 1; and (c) intra-residue interactions. The reliability of the proposed model has been tested by comparing the atomistic and coarse-grained energies calculated for a large number of independent configurations of the beta-helical building block.

Coarse-graining: a procedure to generate equilibrated and relaxed models of amorphous polymers.

We present a coarse-graining procedure to construct models of amorphous polymers. The method, which was applied to polyethylene, is based on a generation-relaxation strategy previously developed to provide independent atomistic microstructures. The coarse-graining was performed by assigning positions to mesoscopic particles denoted blobs, which represent groups of atoms, through distance, angle and dihedral distribution functions. The interaction energy between pairs of blobs was evaluated through a soft potential, whose parameters were derived from atomistic models. Three levels of coarse-graining that differ in the number of atoms included in the blob have been considered. The structural and energy-related properties calculated using the coarse-grained models developed in this study are in good agreement with those obtained using atomistic simulations.

Computational tool to model the packing of polycyclic chains: structural analysis of amorphous polythiophene.

A very efficient computational procedure, which was previously developed to generate and relax atomistic models of linear and comb-like amorphous polymers, has been adapted to model the amorphous phase of polycyclic systems. The strategy, which is a based in a generation algorithm that eliminates the torsion strain and a simple Monte Carlo Metropolis method to relax the generated structures, has been used to predict the density of amorphous polythiophene by combining NVT and NPT simulations. The theoretical value is in the excellent agreement with the experimental one, the former being overestimated by only 3-5%. Next, the molecular conformation and the packing of the rings were studied in detail. Interestingly, the amorphous phase of polythiophene can be described as a packing of elongated molecular chains more or less aligned in the same direction, in which the thiophene rings close in the space but belonging to different chains tend to adopt approximate parallel or antiparallel displaced pi-stacked arrangements.

Force-field parametrization of retro-inverso modified residues: development of torsional and electrostatic parameters.

Torsional and the electrostatic parameters for molecular mechanics studies of retro-inverso modified peptides have been developed using quantum mechanical calculations. The resulting parameters have been compared with those calculated for conventional peptides. Rotational profiles, which were obtained spanning the corresponding dihedral angle, were corrected by removing the energy contributions associated to changes in interactions different from torsion under study. For this purpose, the torsional energy associated to each point of the profiles was estimated as the corresponding quantum mechanical energy minus the bonding and nonbonding energy contributions produced by the perturbations that the variation of the spanned dihedral angle causes in the bond distances, bond angles and the other dihedral angles. These energies were calculated using force-field expressions. The corrected profiles were fitted to a three-term Fourier expansion to derive the torsional parameters. Atomic charges for retro-inverso modified residues were derived from the rigorously calculated quantum mechanical electrostatic potential. Furthermore, the reliability of electrostatic models based on geometry-dependent charges and fixed charges has been examined.

Reliability of the density functional approximation to describe the charge transfer and electrostatic complexes involved in the modeling of organic conducting polymers.

Both the intermolecular interaction energies and the geometries for M... thiophene, M... pyrrole, M(n+)... thiophene, and M(n+)... pyrrole (with M = Li , Na, K, Ca, and Mg; and M(n+) = Li+, Na+, K+, Ca2+, and Mg2+) have been estimated using four commonly used density functional theory (DFT) methods: B3LYP, B3PW91, PBE, and MPW1PW91. Results have been compared to those provided by HF, MP2, and MP4 conventional ab initio methods. The PBE and MPW1PW91 are the only DFT methods able to provide a reasonable description of the M...pi complexes. Regarding M(n+)...pi complexes, the four DFT methods have been proven to be adequate in the prediction of these electrostatically stabilized systems, even though they tend to overestimate the interaction energies.