16,454 research outputs found

    Conformations of 2-phenyl-3-pyridylpropenoic acid (alpha-phenyl pyridylcinnamic acid) dimers – A computational study

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    Motivation. Cinnamic acid analogs are not only important parts of the shikimic acid metabolic pathway of higher plants but it is possible to assemble, particularly from those containing oxygen or nitrogen heteroatoms, various patterned structures kept together with CH...O or CH...N hydrogen bonds. The fundamental unit of these structures is the acid dimer, e.g., the dimer of E and Z–2–phenyl–3–pyridylpropenoic acids of this study, which may exist in many conformations. As a preparation for a detailed conformational analysis of the patterned structures, it was decided to study the conformational behavior of these acid dimers, containing the N heteroatom in all possible positions of the aromatic ring. The conformational behavior of any cinnamic acid analogs in the dimeric form has not been studied before. Method. The conformational search module of the HyperChem package was used for the conformational analysis of the acid dimers with the PM3 semiempirical method. Calculations were performed for isolated dimers, i.e., without solvent. Results. The conformational search identified many conformers of the acid dimers. Although their numbers amounted to hundreds, they were found to fill the conformational space unevenly, in a highly symmetric nature. The distribution patterns were typical for the stereoisomers, but resembled to each other irrespective to the position of the nitrogen atom. Conclusions. It was proved to be possible to study the conformational behavior of cinnamic acid analogs in their dimeric forms for the first time. Large number of conformers was identified and they were found the fill the conformational space in a patterned way

    Peptides binding cocaine: A strategy to design biomimetic receptors

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    A computational methodology for designing and rationalizing the selection of small peptides as biomimetic receptors for cocaine is proposed. The method started by searching and filtering proteins X-ray and NMR data of biological receptor-cocaine complexes. On the basis of different cocaine zones, the amino acids involved in biological binding sites were selected as pivots to design an initial library of 768 penta-peptides. The peptides flexibility was studied determining the minimum number of conformers required to make a reliable computed binding score. The 25 highest ranked penta-peptides were selected and used as starting point to generate a 3000 hexapeptides library by inserting each of the 20 natural amino acids in all sequence positions. All structures were energy minimized and docking runs were carried out using FRED tool from OpenEye scientific. The binding scores calculated by FRED were compared with a preliminary in vivo experimental test, using two different peptides as selective sorbent material used for cocaine in Solid Phase Extraction (SPE) technique coupled with Mass Spectrometry (MS). The simulation data were found to be in agreement with experimental laboratory results, supporting the methodology proposed in this work. © 2013 Perez G, et al

    The Conformational Space of a Flexible Amino Acid at Metallic Surfaces

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    In interfaces between inorganic and biological materials relevant for technological applications, the general challenge of structure determination is exacerbated by the high flexibility of bioorganic components, chemical bonding, and charge rearrangement at the interface. In this paper, we investigate a chemically complex building block, namely, the arginine (Arg) amino-acid interfaced with Cu, Ag and Au (111) surfaces. We investigate how the environment changes the accessible conformational space of this amino acid, by building and analyzing a database of thousands of structures optimized with the PBE functional including screened pairwise van der Waals interactions. When in contact with metallic surfaces, the accessible space for Arg is dramatically reduced, while the one for Arg-H+^+ is instead increased if compared to the gas-phase. This is explained by the formation of strong bonds between Arg and the surfaces and by their absence and charge screening on Arg-H+^+ upon adsorption. We also observe protonation-dependent stereoselective binding of the amino acid to the metal surfaces: Arg adsorbs with its chiral Cα_\alphaH center pointing H away from the surfaces while Arg-H+^+ adsorbs with H pointing toward the surface

    Structural analysis of intrinsically disordered proteins: computer atomistic simulation

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    Intrinsically disordered proteins (IDPs) are biomolecules that do not have a definite 3D structure; their role in the biochemical network of a cell relates to their ability to switch rapidly among different secondary and tertiary structures. For this reason, applying a simulation computer program to their structural study turns out to be problematic, as their dynamical simulation cannot start from a known list of atomistic positions, as is the case for globular proteins that do crystallize and that one can analyse by X-ray spectroscopy to determine their structure. We have established a method to perform a computer simulation of these proteins, apt to gather statistically significant data on their transient structures. The only required input to start the procedure is the primary sequence of the disordered domains of the protein, and the 3D structure of the ordered domains, if any. For a fully disordered protein the method is as follows: (a) The first step is the creation of a multi-rod-like configuration of the molecule, derived from its primary sequence. This structure evolves dynamically in vacuo or in an implicit model of solvent, until its gyration radius - or any other measure of the overall configuration of the molecule - reaches the experimental average value; at this point, one may follow two different paths. (b1) If the study focuses on transient secondary structures of the molecule, one puts the structure obtained at the end of the first step in a box containing solvent molecules in explicit implementation, and a standard molecular dynamics simulation follows. (b2) If the study focuses on the tertiary structure of the molecule, a larger sampling of the phase space is required, with the molecule moving in very large and diverse regions of the phase space. To this end, the structure of the IDP is let evolve dynamically in an implicit solvent using metadynamics, an algorithm that keeps track of the regions of the phase space already sampled, and forces the system to wander in further regions of the phase space. (c) One can increase the accuracy of the statistical information gathered in both cases by fitting, where available, experimental data of the protein. In this step one extracts an ensemble of ’best’ conformers from the pool of all configurations produced in the simulated dynamics. One derives this ensemble by means of an ensemble optimization method, implementing a genetic algorithm. We have applied this procedure to the simulation of tau, one of the largest fully disordered proteins, which is involved in the development of Alzheimer’s disease and of other neurodegenerative diseases. We have combined the results of our simulation with small-angle X-ray scattering experimental data to extract from the dynamics an optimized ensemble of most probable conformers of tau. The method can be easily adapted to IDPs entailing ordered domains

    Application of Computational Chemical Shift Prediction Techniques to the Cereoanhydride Structure Problem-Carboxylate Complications.

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    Despite the vast array of techniques available to modern-day chemists, structural misassignments still occur. These misassignments are often only realized upon attempted synthesis, when the spectra of synthesized products do not match previously reported spectra. This was the case with marine natural product cereoanhydride. The originally proposed 7-membered ring anhydride (1) was shown to be incorrect, although a likely precursor to the correct structure (2) in both its laboratory synthesis and biosynthesis. Herein, in addition to showing how NMR computations could have been used to arrive at the correct structure, we show that the conversion of 1 to 2 is indeed energetically viable, and we highlight complications in predicting NMR chemical shifts for molecules with acidic protons

    Pockets as structural descriptors of EGFR kinase conformations

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    Epidermal Growth Factor Receptor (EGFR), a tyrosine kinase receptor, is one of the main tumor markers in different types of cancers. The kinase native state is mainly composed of two populations of conformers: active and inactive. Several sequence variations in EGFR kinase region promote the differential enrichment of conformers with higher activity. Some structural characteristics have been proposed to differentiate kinase conformations, but these considerations could lead to ambiguous classifications. We present a structural characterisation of EGFR kinase conformers, focused on active site pocket comparisons, and the mapping of known pathological sequence variations. A structural based clustering of this pocket accurately discriminates active from inactive, well-characterised conformations. Furthermore, this main pocket contains, or is in close contact with, ≈65% of cancer-related variation positions. Although the relevance of protein dynamics to explain biological function has been extensively recognised, the usage of the ensemble of conformations in dynamic equilibrium to represent the functional state of proteins and the importance of pockets, cavities and/or tunnels was often neglected in previous studies. These functional structures and the equilibrium between them could be structurally analysed in wild type as well as in sequence variants. Our results indicate that biologically important pockets, as well as their shape and dynamics, are central to understanding protein function in wild-type, polymorphic or disease-related variations.Fil: Hasenahuer, Marcia AnahĂ­. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂ­a; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Barletta Roldan, Patricio German. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂ­a; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: FernĂĄndez Alberti, SebastiĂĄn. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂ­a; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Parisi, Gustavo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂ­a; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Fornasari, Maria Silvina. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂ­a; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; Argentin