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Polar Interactions (polar + interaction)
Selected AbstractsABSINTH: A new continuum solvation model for simulations of polypeptides in aqueous solutionsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 5 2009Andreas Vitalis Abstract A new implicit solvation model for use in Monte Carlo simulations of polypeptides is introduced. The model is termed ABSINTH for self- Assembly of Biomolecules Studied by an Implicit, Novel, and Tunable Hamiltonian. It is designed primarily for simulating conformational equilibria and oligomerization reactions of intrinsically disordered proteins in aqueous solutions. The paradigm for ABSINTH is conceptually similar to the EEF1 model of Lazaridis and Karplus (Proteins 1999, 35, 133). In ABSINTH, the transfer of a polypeptide solute from the gas phase into a continuum solvent is the sum of a direct mean field interaction (DMFI), and a term to model the screening of polar interactions. Polypeptide solutes are decomposed into a set of distinct solvation groups. The DMFI is a sum of contributions from each of the solvation groups, which are analogs of model compounds. Continuum-mediated screening of electrostatic interactions is achieved using a framework similar to the one used for the DMFI. Promising results are shown for a set of test cases. These include the calculation of NMR coupling constants for short peptides, the assessment of the thermal stability of two small proteins, reversible folding of both an ,-helix and a ,-hairpin forming peptide, and the polymeric properties of intrinsically disordered polyglutamine peptides of varying lengths. The tests reveal that the computational expense for simulations with the ABSINTH implicit solvation model increase by a factor that is in the range of 2.5,5.0 with respect to gas-phase calculations. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009 [source] WATGEN: An algorithm for modeling water networks at protein,protein interfacesJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 14 2007Huynh-Hoa Bui Abstract Water molecules at protein,protein interfaces contribute to the close packing of atoms and ensure complementarity between the protein surfaces, as well as mediating polar interactions. Therefore, modeling of interface water is of importance in understanding the structural basis of biomolecular association. We present an algorithm, WATGEN, which predicts locations for water molecules at a protein,protein or protein,peptide interface, given the atomic coordinates of the protein and peptide. A key element of the WATGEN algorithm is the prediction of water sites that can form multiple hydrogen bonds that bridge the binding interface. Trial calculations were performed on water networks predicted by WATGEN at 126 protein,peptide interfaces (X-ray resolutions , 2.0 Å), using different criteria for water placement. The energies of the predicted water networks were evaluated in AMBER8 and used in the choice of parameters for WATGEN. The 126 interfaces include 1264 experimentally determined bridging water sites, and the WATGEN algorithm predicts 72 and 88% of these sites within 1.5 and 2.0 Å, respectively. The predicted number of water molecules at each interface was much higher than the number of water molecules identified experimentally. Therefore, random placement of the same number of water molecules as that predicted at each interface was performed as a control, and resulted in only 22 and 40% of water sites placed within 1.5 and 2.0 Å of experimental sites, respectively. Based on these data, we conclude that WATGEN can accurately predict the location of water molecules at a protein,peptide interface, and this may be of value for understanding the energetics and specificity of biomolecular association. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2007 [source] Polymer Chain Collapse in Supercritical Fluids.MACROMOLECULAR SYMPOSIA, Issue 1 2009Abstract The phase behavior of a polymer in a supercritical solvent at the LCST equilibrium limits is described in this work, in the proximity of , point, proposing the use of a conformational parameter, ,. The results obtained by molecular simulation in an NVT ensemble have been correlated by extensive, varied experimental information. The relationship between polymer/solvent solubility parameters has shown that the behavior of these systems is a function of the energetic structure-interaction relationship between the polymer chain and the solvent. , results in a generalized parameter indicative of the phase stability of the solution. At greater magnitudes, the solution becomes unstable, requiring elevated pressure to stabilize. However, stable solutions are found at lower pressures when , approaches 1. The experimental evidence, together with the determination of the solubility parameter with the Sanchez-Lacombe equation (also obtained from the literature) strengthens this observation. The analysis of the polar contribution on the Hansen Parameter (HSP) enables their effect to be studied in systems where high polar interactions between the polymer and solvent (as in the case of biopolymers) are expected. [source] Liposome/water lipophilicity: Methods, information content, and pharmaceutical applicationsMEDICINAL RESEARCH REVIEWS, Issue 3 2004Georgette Plemper van Balen Abstract This review discusses liposome/water lipophilicity in terms of the structure of liposomes, experimental methods, and information content. In a first part, the structural properties of the hydrophobic core and polar surface of liposomes are examined in the light of potential interactions with solute molecules. Particular emphasis is placed on the physicochemical properties of polar headgroups of lipids in liposomes. A second part is dedicated to three useful methods to study liposome/water partitioning, namely potentiometry, equilibrium dialysis, and 1H-NMR relaxation rates. In each case, the principle and limitations of the method are discussed. The next part presents the structural information encoded in liposome/water lipophilicity, in other words the solutes' structural and physicochemical properties that determine their behavior and hence their partitioning in such systems. This presentation is based on a comparison between isotropic (i.e., solvent/water) and anisotropic (e.g., liposome/water) systems. An important factor to be considered is whether the anisotropic lipid phase is ionized or not. Three examples taken from the authors' laboratories are discussed to illustrate the factors or combinations thereof that govern liposome/water lipophilicity, namely (a) hydrophobic interactions alone, (b) hydrophobic and polar interactions, and (c) conformational effects plus hydrophobic and ionic interactions. The next part presents two studies taken from the field of QSAR to exemplify the use of liposome/water lipophilicity in structure,disposition and structure,activity relationships. In the conclusion, we summarize the interests and limitations of this technology and point to promising developments. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 3, 299,324, 2004 [source] Quantitative Structure,Activity Relationship Studies for the Binding Affinities of Imidazobenzodiazepines for the ,6 Benzodiazepine Receptor Isoform Utilizing Optimized Blockwise Variable Combination by Particle Swarm Optimization for Partial Least Squares ModelingMOLECULAR INFORMATICS, Issue 1 2007Leqian Hu Abstract Binding affinities of a series of substituted imidazobenzodiazepines for the ,6 Benzodiazepine Receptor (BzR) isoform are investigated by the Optimized Blockwise Variable Combination (OBVC) by Particle Swarm Optimization (PSO) based on Partial Least Squares (PLS) modeling. The QSAR analysis result showed that MolRef, AlogP, MRCM**-3, Rotatable bonds (Rotlbonds), Hydrogen Bond Acceptors (Hbond acceptor), five Jurs descriptors, two Shadow indices descriptors and principal moment of inertia are the most important descriptors among all the investigated descriptors. One can change the molar refractivity, the polar interactions between molecules, the shape of the molecules, the principal moments of inertia about the principal axes of a molecule, the hydrophobic character of the molecule, the number of Rotlbonds and Hbond acceptors of the compounds to adjust the binding affinities of imidazobenzodiazepine for the ,6 BzR isoform. The Quantitative Structure,Activity Relationship (QSAR) analysis result was also compared with MLR, PLS, and hierarchical PLS algorithms. It has been demonstrated that OBVC by PSO for PLS modeling shows satisfactory performance in the QSAR analysis. [source] The hemoglobins of the trematodes Fasciola hepatica and Paramphistomum epiclitum: A molecular biological, physico-chemical, kinetic, and vaccination studyPROTEIN SCIENCE, Issue 10 2008Sylvia Dewilde Abstract The trematode Fasciola hepatica (Fa.he.) is a common parasite of human and livestock. The hemoglobin (Hb) of Fa.he., a potential immunogen, was chosen for characterization in the search for an effective vaccine. Characterization of trematode Hbs show that they are intracellular single-domain globins with the following remarkable features: (1) Fa.he. expresses two Hb isoforms that differ at two amino acid sites (F1: 119Y/123Q; F2: 119F/123L). Both isoforms are monoacetylated at their N-termini; (2) the genes coding for Fa.he. and Paramphistomum epiclitum (Pa.ep.) Hbs are interrupted by two introns at the conserved positions B12.2 and G7.0.; (3) UV/VIS and resonance Raman spectroscopy identify the recombinant Fa.he. HbF2 as a pentacoordinated high-spin ferrous Hb; (4) electron paramagnetic resonance spectroscopy of cyano-met Fa.he. HbF2 proves that the endogenously bound imidazole has no imidazolate character; (5) the major structural determinants of the globin fold are present, they contain a TyrB10/TyrE7 residue pair on the distal side. Although such distal-site pair is a signature for high oxygen affinity, as shown for Pa.ep. Hb, the oxygen-binding rate parameters for Fa.he. Hb are intermediate between those of myoglobin and those of other trematode Hbs; (6) the three-dimensional structure of recombinant Fa.he. HbF2 from this study closely resembles the three-dimensional structure of Pa.ep. determined earlier. The set of distal-site polar interactions observed in Pa.ep. Hb is matched with small but significant structural adjustments; (7) despite the potential immunogenic character of the fluke Hb, vaccination of calves with recombinant Fa.he. HbF2 failed to promote protection against parasitic infection. [source] How do helix,helix interactions help determine the folds of membrane proteins?PROTEIN SCIENCE, Issue 4 2003Perspectives from the study of homo-oligomeric helical bundles FRET, fluorescence resonance energy transfer; NBD, 7-nitrobenz-2-oxa-1,3-diazole; C-14 betaine, N -tetradecyl- N,N -dimethyl-3-ammonio-1-propanesulfonate; MF, mole fraction Abstract The final, structure-determining step in the folding of membrane proteins involves the coalescence of preformed transmembrane helices to form the native tertiary structure. Here, we review recent studies on small peptide and protein systems that are providing quantitative data on the interactions that drive this process. Gel electrophoresis, analytical ultracentrifugation, and fluorescence resonance energy transfer (FRET) are useful methods for examining the assembly of homo-oligomeric transmembrane helical proteins. These methods have been used to study the assembly of the M2 proton channel from influenza A virus, glycophorin, phospholamban, and several designed membrane proteins,all of which have a single transmembrane helix that is sufficient for association into a transmembrane helical bundle. These systems are being studied to determine the relative thermodynamic contributions of van der Waals interactions, conformational entropy, and polar interactions in the stabilization of membrane proteins. Although the database of thermodynamic information is not yet large, a few generalities are beginning to emerge concerning the energetic differences between membrane and water-soluble proteins: the packing of apolar side chains in the interior of helical membrane proteins plays a smaller, but nevertheless significant, role in stabilizing their structure. Polar, hydrogen-bonded interactions occur less frequently, but, nevertheless, they often provide a strong driving force for folding helix,helix pairs in membrane proteins. These studies are laying the groundwork for the design of sequence motifs that dictate the association of membrane helices. [source] Ligand binding at the transthyretin dimer,dimer interface: structure of the transthyretin,T4Ac complex at 2.2,Å resolutionACTA CRYSTALLOGRAPHICA SECTION D, Issue 10 2005Vivian Cody The crystal structure of the complex of human transthyretin (hTTR) with 3,3,,5,5,-tetraiodothyroacetic acid (T4Ac) has been determined to 2.2,Å resolution. The complex crystallizes in the orthorhombic space group P21212, with unit-cell parameters a = 43.46, b = 85.85, c = 65.44,Å. The structure was refined to R = 17.3% and Rfree = 21.9% for reflections without any ,-cutoff. T4Ac is bound in both the forward and the reverse mode in the two binding sites of hTTR. In the forward orientation, T4Ac binds in a position similar to that described for thyroxine (T4) in the orthorhombic hTTR,T4 complex. In this orientation, the iodine substituents of the phenolic ring are bound in the P3,/P2 halogen pockets. In the reverse orientation, which is the major binding mode of T4Ac, the ligand is bound deep in the TTR channel, with the carboxylic group bound in the P3, pocket and forming simultaneous polar interactions with the residues constituting the two hormone-binding sites. Such interactions of a thyroxine-analogue ligand bound in the reverse mode have never been observed in TTR complexes previously. [source] Structure of interleukin 4 mutant E9A suggests polar steering in receptor-complex formationACTA CRYSTALLOGRAPHICA SECTION D, Issue 9 2001Martin Hülsmeyer Interleukin 4 (IL-4) is a pleiotropic cytokine which induces T-cell differentiation and class switching of B cells. It therefore plays a central role in the development of allergies and asthma. An IL-4 variant in which Glu9 was mutated to alanine shows an 800-fold drop in binding affinity towards its high-affinity receptor chain. As shown by surface plasmon resonance measurements, this mostly arises from a decreased association rate. Here, the crystal structure of this mutant is reported. It reveals that the protein has a virtually identical structure to the wild type, showing that the unusual behaviour of the mutated protein is not a consequence of misfolding. The possibility that polar interactions in the encounter complex have a steering effect is discussed. [source] Bioanalysis of pentoxifylline and related metabolites in plasma samples through LC-MS/MSBIOMEDICAL CHROMATOGRAPHY, Issue 6 2010Daniela Iuliana Sora Abstract Analytical aspects related to the assay of pentoxifylline (PTX), lisofylline (M1) and carboxypropyl dimethylxanthine (M5) metabolites are discussed through comparison of two alternative analytical methods based on liquid chromatography separation and atmospheric pressure electrospray ionization tandem mass spectrometry detection. One method is based on a ,pure' reversed-phase liquid chromatography mechanism, while the second one uses the additional polar interactions with embedded amide spacers linking octadecyl moieties to the silicagel surface (C-18 Aqua stationary phase). In both cases, elution is isocratic. Both methods are equally selective and allows separation of unknowns (four species associated to PTX, two species associated to M1) detected through specific mass transitions of the parent compounds and owning respective structural confirmation. Plasma concentration,time patterns of these compounds follow typical metabolic profiles. It has been advanced that in-vivo formation of conjugates of PTX and M1 is possible, such compounds being cleaved back to the parent ones within the ion source. The first method was associated with a sample preparation procedure based on plasma protein precipitation by strong organic acid addition. The second method used protein precipitation by addition of a water miscible organic solvent. Both analytical methods were fully validated and used to assess bioequivalence between a prolonged release generic formulation and the reference product, under multidose and single dose approaches. Copyright © 2009 John Wiley & Sons, Ltd. [source] Modeling of the Intestinal Peptide Transporter hPepT1 and Analysis of Its Transport Capacities by Docking and Pharmacophore MappingCHEMMEDCHEM, Issue 12 2008Alessandro Pedretti Dr. Abstract An early pharmacokinetic screen for peptidomimetic drugs should have the ability to predict molecules with high affinity for intestinal transporters, as peptide-like derivatives are seldom absorbed passively. Hence, the first objective of this study was to generate a reliable model for the structure of the hPepT1 protein, which is the main intestinal transporter involved in the absorption of both dietary peptides and peptidomimetics. The modeling was based on the resolved structure of the homologous bacterial lactose permease LacY using a fragmental strategy. The interaction capacities of the hPepT1 model were explored by docking a set of 50 known ligands. Despite the known predilection of hPepT1 for hydrophobic ligands, docking results unveiled the key role of the polar interactions stabilized by charged termini, especially concerning the ammonium head group. The docking results were further verified by developing a pharmacophore model that confirmed the key features required for optimal hPepT1 affinity. The consistency of the docking results and the agreement with the pharmacophore model afford an encouraging validation for the proposed model and suggest that it can be exploited to design peptide-like molecules with an improved affinity for such a transporter. [source] | ||||||||||