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David Zanuy

Publications and source records attributed to David Zanuy.

At least 19 recordsLinked to original sources
PubMed2007

Contraction process of an electroactive actuator based on a one microsecond atomistic molecular dynamics simulation.

The contraction process of an electroactive actuator constituted by calix[4]arene units and quaterthiophene segments has been investigated at the microscopic level by using atomistic molecular dynamics simulations in dichloromethane solution using explicit solvent molecules. Results derived from a 1 mus trajectory of the oxidized and deprotonated actuator indicate that the contraction occurs through a non-concerted mechanism in which each actuating units present in the system behave independently. The efficiency of the contraction process can be reduced by the presence of secondary conformational transitions in the calix[4]arene scaffolds. Accordingly, the drastic reduction of the molecular length expected during the contraction process can be limited by such transitions, which involve the rotational isomerism of a phenolate ring. However, such type of conformational transitions does not compromise the actuator power due to its intrinsic capacity to adopt compact molecular arrangements. On the other hand, the rate of the contraction process is influenced by the presence of solvent molecules, which have been found to reduce it by a factor of about 1000.

Calixarenes↗
PubMed2006

Backbone conformational preferences and pseudorotational ring puckering of 1-aminocyclopentane-1-carboxylic acid.

We have used quantum mechanical calculations at the B3LYP/6-311G(d,p) level to determine the conformational preferences of the N-acetyl-N'-methylamide derivative of 1-aminocyclopentane-1-carboxylic acid in the gas phase, chloroform solution, and water solution. The backbone conformation of this dipeptide has been described through the dihedral angles varphi and psi, while the pseudorotational phase angle was used to define the conformation of the cyclopentane ring. Results indicate that the backbone flexibility of this amino acid is restricted by the cyclic nature of the side chain, the relative stability of the different conformations depending on the polarity of the environment. The potential energy of the pseudorotation was also studied as a function of the backbone conformation. Interestingly, the conformation of the cyclic side chain depends on the backbone arrangement. Furthermore, the number of pseudorotational states accessible at room temperature is high in all the investigated environments, especially in aqueous solution. Finally, a set of force-field parameters for classical molecular mechanics calculations was developed for the investigated amino acid. Molecular dynamics simulations in both chloroform and aqueous solutions were performed to demonstrate the reliability of such parameters.

Computer Simulation↗
PubMed2006

Conformational isomerism of electroactive calix[4]arenes: influence of the electronic state in the flexibility of thiophene-containing calix[4]arene.

The cone-to-paco conformational isomerism of 11,23-bis(thiophen-5-yl)-26,28-dimethoxycalix[4]arene-25,27-diol, a calix[4]arene with thiophene substituents in para position with respect to the hydroxyl groups, has been investigated using ab initio and DFT quantum mechanical methods. This compound models a molecular device constituted by small oligomers of thiophene and calix[4]arene units, whose actuation mechanism is promoted by the conformational flexibility of the latter. To examine the influence of the electronic structure of this electroactive calix[4]arene, three different states have been considered: (i) neutral state; (ii) oxidized state, in which one electron is extracted from each thiophene ring; and (iii) oxidized-deprotonated state, in which the two hydroxyl groups of the oxidized compound are deprotonated. Results are discussed and compared with those obtained for the same molecule but without thiophene substituents, 25,27-dihydroxy-26,28-dimethoxycalix[4]arene. Although the influence of the thiophene substituents is negligible in the neutral state, they play a crucial role in the rotational isomerism of both the oxidized and deprotonated-oxidized states.

Journal Article↗
PubMed2006

Conformational features of an actuator containing calix[4]arene and thiophene: a molecular dynamics study.

Molecular dynamics simulations have been performed for poly(calix[4]arene bis(bithiophene)) in dichloromethane solution. This material responds to its electronic structure variations with significant conformational changes, producing contraction-expansion movements. Simulations have been performed for the three states of this molecular actuator (reduced, oxidized-nondeprotonated, and oxidized-deprotonated), a specific force-field being developed for each case. Results, which are fully consistent with previous ab initio quantum mechanical calculations on an isolated actuating unit, have revealed important findings about the dynamics of the system. Analyses of the flexibility/rigidity of the molecular chain with the state, the interaction of the polymer with the solvent molecules and the influence of environmental factors (as the viscosity of solvent, the counterions and the thermal agitation) on the dynamics have provided important insights to the actuation mechanism.

Journal Article↗
PubMed2006

From peptide-based material science to protein fibrils: discipline convergence in nanobiology.

This paper illustrates the merits of convergence in nanobiology of two seemingly disparate fields, material science and computational biology. Traditionally, material science has been a discipline involving design and fabrication of synthetic polymers consisting of repeating units. Collaboration with synthetic organic chemists allowed design of new polymers, with a range of altered conformations. Yet, naturally occurring proteins are also materials. Their varied sequences and structures should enrich material science providing more complex shapes, scaffolds and chemical properties. For material scientists, the enhanced coverage of chemical space obtained by integrating proteins and synthetic organic chemistry through the introduction of non-natural residues allows a range of new useful potential applications.

Biocompatible Materials↗
PubMed2006

Concepts and schemes for the re-engineering of physical protein modules: generating nanodevices via targeted replacements with constrained amino acids.

Physically building complex multi-molecular structures from naturally occurring biological macromolecules has aroused a great deal of interest. Here we focus on nanostructures composed of re-engineered, natural 'foldamer' building blocks. Our aim is to provide some of the underlying concepts and schemes for crafting structures utilizing such conformationally relatively stable molecular components. We describe how, via chemical biology strategies, it is further possible to chemically manipulate the foldamer building blocks toward specific shape-driven structures, which in turn could be used toward potential-designed functions. We outline the criteria in choosing candidate foldamers from the vast biological repertoire, and how to enhance their stability through selected targeted replacements by non-proteinogenic conformationally constrained amino acids. These approaches combine bioinformatics, high performance computations and mathematics with synthetic organic chemistry. The resulting artificially engineered self-organizing molecular scale structures take advantage of nature's nanobiology toolkit and at the same time improve on it, since their new targeted function differs from that optimized by evolution. The major challenge facing nanobiology is to be able to exercise fine control over the performance of these target-specific molecular machines.

Combinatorial Chemistry Techniques↗
PubMed2006

Computational study of the fibril organization of polyglutamine repeats reveals a common motif identified in beta-helices.

The formation of fibril aggregates by long polyglutamine sequences is assumed to play a major role in neurodegenerative diseases such as Huntington. Here, we model peptides rich in glutamine, through a series of molecular dynamics simulations. Starting from a rigid nanotube-like conformation, we have obtained a new conformational template that shares structural features of a tubular helix and of a beta-helix conformational organization. Our new model can be described as a super-helical arrangement of flat beta-sheet segments linked by planar turns or bends. Interestingly, our comprehensive analysis of the Protein Data Bank reveals that this is a common motif in beta-helices (termed beta-bend), although it has not been identified so far. The motif is based on the alternation of beta-sheet and helical conformation as the protein sequence is followed from the N to the C termini (beta-alpha(R)-beta-polyPro-beta). We further identify this motif in the ssNMR structure of the protofibril of the amyloidogenic peptide Abeta(1-40). The recurrence of the beta-bend suggests a general mode of connecting long parallel beta-sheet segments that would allow the growth of partially ordered fibril structures. The design allows the peptide backbone to change direction with a minimal loss of main chain hydrogen bonds. The identification of a coherent organization beyond that of the beta-sheet segments in different folds rich in parallel beta-sheets suggests a higher degree of ordered structure in protein fibrils, in agreement with their low solubility and dense molecular packing.

Amino Acid Motifs↗
PubMed2006

De novo tubular nanostructure design based on self-assembly of beta-helical protein motifs.

We present an approach for designing self-assembled nanostructures from naturally occurring building block segments obtained from native protein structures. We focus on structural motifs from left-handed beta-helical proteins. We selected 17 motifs. Copies of each of the motifs are stacked one atop the other. The obtained structures were simulated for long periods by using Molecular Dynamics to test their ability to retain their organization over time. We observed that a structural model based on the self-assembly of a motif from E. coli galactoside acetyltransferase produced a very stable tube. We studied the interactions that help maintain the conformational stability of the systems, focusing on the role of specific amino acids at specific positions. Analysis of these systems and a mutational study of selected candidates revealed that the presence of proline and glycine residues in the loops of beta-helical structures greatly enhances the structural stability of the systems.

Acetyltransferases↗
PubMed2005

Systematic evaluation of the conformational properties of aliphatic omega-hydroxy acids.

A systematic conformational study of omega-hydroxy acids, HO-(CH(2))(n)()-COOH with n ranging from 2 to 5, has been performed using quantum mechanical calculations at the MP2 level. To distinguish between intrinsic and environmentally induced conformational preferences, calculations have been carried out in both gas phase and chloroform solution, a polarizable continuum solvation model being used to represent the latter. Results indicate a consistent conformational behavior, as reflects the feature that the lowest energy minimum for n = 2, 3, 4, and 5 corresponds to the g+g-t, g+g+g-t, g-g+g+g-t, and g+g-g+g+g-t conformations, respectively. Furthermore, the stability of the extended and semi-extended conformations increases systematically with the size of the central aliphatic segment. The relationship between the size of the aliphatic segment and the stability of folded conformations is analyzed and discussed.

Journal Article↗
PubMed2004

A comparative study of amyloid fibril formation by residues 15-19 of the human calcitonin hormone: a single beta-sheet model with a small hydrophobic core.

Experimentally, the human calcitonin hormone (hCT) can form highly stable amyloid protofibrils. Further, a peptide consisting of hCT residues 15-19, DFNKF, was shown to create highly ordered fibrils, similar to those formed by the entire hormone sequence. However, there are limited experimental data regarding the detailed 3D arrangement of either of these fibrils. We have modeled the DFNKF protofibril, using molecular dynamics simulations. We tested the stabilities of single sheet and of various multi sheet models. Remarkably, our most ordered and stable model consists of a parallel-stranded, single beta-sheet with a relatively insignificant hydrophobic core. We investigate the chemical and physical interactions responsible for the high structural organization of this single beta-sheet amyloid fibril. We observe that the most important chemical interactions contributing to the stability of the DFNKF organization are electrostatic, specifically between the Lys and the C terminus, between the Asp and N terminus, and a hydrogen bond network between the Asn side-chains of adjacent strands. Additionally, we observe hydrophobic and aromatic pi stacking interactions. We further simulated truncated filaments, FNKF and DFNK. Our tetra-peptide mutant simulations assume models similar to the penta-peptide. Experimentally, the FNKF does not create fibrils while DFNK does, albeit short and less ordered than DFNKF. In the simulations, the FNKF system was less stable than the DFNK and DFNKF. DFNK also lost many of its original interactions becoming less organized, however, many contacts were maintained. Thus, our results emphasize the role played by specific amino acid interactions. To further study specific interactions, we have mutated the penta-peptide, simulating DANKF, DFNKA and EFNKF. Here we describe the model, its relationship to experiment and its implications to amyloid organization.

Amino Acid Sequence↗
PubMed2004

Thermal stability of the secondary structure of poly(alpha,L-glutamate) in self-assembled complexes as studied by molecular dynamics in chloroform solution.

The thermal stability of the self-assembled complexes formed by alkyltrimethylammonium surfactants and poly(alpha,l-glutamate) is investigated in dilute chloroform solution by molecular dynamics simulations. By applying temperatures ranging from 300 to 500 K, we observed an extraordinary stability of the alpha-helix adopted by the polypeptide during a total of 48 ns. The multiple electrostatic interactions formed between the surfactant chains and the polyanion play a crucial role in this stability since they are responsible for the inaccessibility of the solvent molecules to the helix even at high temperatures.

Chloroform↗
PubMed2004

Peptide sequence and amyloid formation; molecular simulations and experimental study of a human islet amyloid polypeptide fragment and its analogs.

We present a combined experimental and theoretical investigation of the tendencies to form amyloid fibrils by a hexapeptide derivative of the human islet amyloid polypeptide, the NFGAIL (22-27) fragment and its mutants. We performed a complete alanine scan of this fragment and studied the capability of the wild-type and its mutant analogs to form ordered fibrils by ultrastructural and biophysical analyses. In parallel, we conducted a meticulous characterization of each sequence-complex at an atomistic level by performing nine independent molecular dynamics simulations for a total of 36 ns. These allowed us to rationalize the experimental observations and to establish the role of every residue in the fibrillogenesis. The main factor that determines the formation of regular fibrils is a coherent organization of the intersheet space. In particular, phenylalanine side chains cement the macromolecular assemblies due to their aromatic chemical character and restricted conformational flexibility when interacting with aliphatic residues.

Alanine↗
PubMed2004

Insights into amyloid structural formation and assembly through computational approaches.

Amyloids are long, insoluble ordered fibers. Due to their insolubility, to date the determination of an amyloid structure with an atomic scale resolution has proven to be a difficult task. Under such circumstances, computational approaches are a preferred option, providing the means to build likely models, test their stabilities and figure out the chemistry of their prevailing interactions. Computational models can be validated by targeted experiments, such as introducing mutations and testing for amyloid formation. Computations further provide vehicles for the comprehension of the mechanisms of amyloid seed formation and oligomer toxicity. Nevertheless, computations face an immense hurdle, the outcome of the time scales involved in amyloid formation and the immense sizes of the systems. In an attempt to overcome these, we adopt a strategy that encompasses (1) bioinformatics studies of native proteins containing beta-sheet structures; (2) simulations of shorter peptides; and finally (3) construction of potential oligomeric models and tests of their stabilities. The results are correlated with experimental data where available. Here, we describe the computational methods in simple terms and present an overview of the results. The systems derive from amyloidogenic, disease-related proteins, including gelsolin, beta2-microglobulin, and peptides derived from the prion, Alzheimer's Abeta, IAPP and human calcitonin. Ultimately, obtaining molecular structures should facilitate efforts to therapy and drug design.

Amyloid↗
PubMed2004

Side chain interactions determine the amyloid organization: a single layer beta-sheet molecular structure of the calcitonin peptide segment 15-19.

In this paper we present a detailed atomic model for a protofilament, the most basic organization level, of the amyloid fibre formed by the peptide DFNKF. This pentapeptide is a segment derived from the human calcitonin, a natural amyloidogenic protein. Our model, which represents the outcome of extensive explicit solvent molecular dynamics (MD) simulations of different strand/sheet organizations, is a single beta-sheet filament largely without a hydrophobic core. Nevertheless, this structure is capable of reproducing the main features of the characteristic amyloid fibril organization and provides clues to the molecular basis of its experimental aggregation behaviour. Our results show that the side chains' chemical diversity induces the formation of a complex network of interactions that finally determine the microscopic arrangement of the strands at the protofilament level. This network of interactions, consisting of both side chain-side chain and backbone-side chain interactions, confers on the final single beta-sheet arrangement an unexpected stability, both by enhancing the association of related chemical groups and, at the same time, by shielding the hydrophobic segments from the polar solvent. The chemical physical characterization of this protofilament provides hints to the possible thermodynamical basis of the supra molecular organization that allows the formation of the filaments by lateral association of the preformed protofibrils. Its regular, highly polarized structure shows how other protofilaments can assemble. In terms of structural biology, our results clearly indicate that an amyloid organization implies a degree of complexity far beyond a simple nonspecific association of peptide strands via amide hydrogen bonds.

Amino Acid Sequence↗
PubMed2004

The stability and dynamics of the human calcitonin amyloid peptide DFNKF.

The stability and dynamics of the human calcitonin-derived peptide DFNKF (hCT(15-19)) are studied using molecular dynamics (MD) simulations. Experimentally, this peptide is highly amyloidogenic and forms fibrils similar to the full length calcitonin. Previous comparative MD studies have found that the parallel beta-stranded sheet is a stable organization of the DFNKF protofibril. Here, we probe the stability and dynamics of the small parallel DFNKF oligomers. The results show that even small DFNKF oligomers, such as trimers and tetramers, are stable for a sufficient time in the MD simulations, indicating that the crucial nucleus seed size for amyloid formation can be quite small. The simulations also show that the stability of DFNKF oligomers increases with their sizes. The small but stable seed may reflect the experimental rapid formation of the DFNKF fibrils. Further, a noncooperative process of parallel beta-sheet formation from the out-of-register trimer is observed in the simulations. In general, the residues of DFNKF peptides near the N-/C-termini are more flexible, whereas the interior residues are more stable. Simulations of mutants and capped peptides show that both interstrand hydrophobic and electrostatic interactions play important roles in stabilizing the DFNKF parallel oligomers. This study provides insights into amyloid formation.

Amyloid↗
PubMed2003

EVEBAT: a fast strategy for the examination of the empty space in polymer matrices.

A very efficient strategy to evaluate the "free volume" and the "unoccupied volume" in polymer matrices is proposed. The method, which has been denoted EVEBAT (Empty Volume Evaluation Based on Atom-Types), emerges from the concept of atom type, which is the basis of a force field. Accordingly, the numerical treatment is minimized by analyzing the atom types used to describe the polymer matrix, which are always a few, rather than all the explicit, atoms involved in it. The performance of the new method has been pointed out by a detailed comparison with the classical insertion algorithms.

Journal Article↗
PubMed2003

The sequence dependence of fiber organization. A comparative molecular dynamics study of the islet amyloid polypeptide segments 22-27 and 22-29.

Amyloid fiber formation and the possible polymorphism of molecular arrangements depend on the polypeptide length and composition. Here, we seek the chemical clues underlying these processes. Our starting point is based on the experimental observation that some short peptide segments are able to develop fibers that are very similar to those of their original parent proteins. We focus our study on the NFGAILSS peptide, derived from the human islet amyloid polypeptide (residues 22-29). This peptide turned out to be a perfect example, illustrating the fact that the amyloid microscopic organization is highly complex, rather than simply involving hydrogen bond formation. Furthermore, obtaining a reliable molecular model has allowed us to analyze the differences between the amyloid structure we have obtained for this peptide and that obtained for the previously studied, two residues shorter, segment (residues 22-27, NFGAIL). This comparative study yields some clues about chemical events that govern the aggregation of proteins into oriented fibers, such as molecular packing between sheets and the degree of interaction specificity. We characterize the important role played by the hydrophobic and aromatic residues in the inter-sheet association and present new approaches toward the understanding of the nature of events that are likely to take place during fibril formation. These include analysis of interaction patterns derived from specific sheet-associated packing.

Amino Acid Sequence↗