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Conformational Search (conformational + search)
Selected AbstractsConformational search of peptides and proteins: Monte Carlo minimization with an adaptive bias method applied to the heptapeptide deltorphinJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 4 2004S. Banu Ozkan Abstract The energy function of a protein consists of a tremendous number of minima. Locating the global energy minimum (GEM) structure, which corresponds approximately to the native structure, is a severe problem in global optimization. Recently we have proposed a conformational search technique based on the Monte Carlo minimization (MCM) method of Li and Scheraga, where trial dihedral angles are not selected at random within the range [,180°,180°] (as with MCM) but with biased probabilities depending on the increased structure-energy correlations as the GEM is approached during the search. This method, called the Monte Carlo minimization with an adaptive bias (MCMAB), was applied initially to the pentapeptide Leu-enkephalin. Here we study its properties further by applying it to the larger peptide with bulky side chains, deltorphin (H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2). We find that on average the number of energy minimizations required by MCMAB to locate the GEM for the first time is smaller by a factor of approximately three than the number required by MCM,in accord with results obtained for Leu-enkephalin. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 565,572, 2004 [source] Solution, solid phase and computational structures of apicidin and its backbone-reduced analogsJOURNAL OF PEPTIDE SCIENCE, Issue 6 2006Michael Kranz Abstract The recently isolated broad-spectrum antiparasitic apicidin (1) is one of the few naturally occurring cyclic tetrapeptides (CTP). Depending on the solvent, the backbone of 1 exhibits two ,-turns (in CH2Cl2) or a ,-turn (in DMSO), differing solely in the rotation of the plane of one of the amide bonds. In the X-ray crystal structure, the peptidic COs and NHs are on opposite sides of the backbone plane, giving rise to infinite stacks of cyclotetrapeptides connected by three intermolecular hydrogen bonds between the backbones. Conformational searches (Amber force field) on a truncated model system of 1 confirm all three backbone conformations to be low-energy states. The previously synthesized analogs of 1 containing a reduced amide bond exhibit the same backbone conformation as 1 in DMSO, which is confirmed further by the X-ray crystal structure of a model system of the desoxy analogs of 1. This similarity helps in explaining why the desoxy analogs retain some of the antiprotozoal activities of apicidin. The backbone-reduction approach designed to facilitate the cyclization step of the acyclic precursors of the CTPs seems to retain the conformational preferences of the parent peptide backbone. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd. [source] Macrocyclic Cyclo[n]malonates , Synthetic Aspects and Observation of Columnar Arrangements by X-ray CrystallographyEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 10 2006Nikos Chronakis Abstract A variety of achiral and chiral macrocyclic oligomalonates were synthesised in a one-step procedure through condensation of malonyl dichloride with ,,,-diols. We have investigated the applicability of this method by varying the length and type of the spacers in the diol. Product distribution analysis revealed that the preferential formation of monomeric, dimeric, or trimeric macrocyclic malonates can be controlled by choosing diols with specific spacers connecting the hydroxy groups. Of special interest are the macrocyclic bismalonates, as they show pronounced crystallisability and arrange into columnar motifs in the solid state. They feature distinctive dihedral angles: all ester moieties adopt anti conformations whereas the planes of the carboxy moieties of each malonate residue arrange in an approximately orthogonal fashion. The latter geometry is enforced by the macrocyclic structures, as revealed by a conformational search in the Cambridge Structural Database. The X-ray diffraction data show that C=O···H,C, and C,O···H,C hydrogen bonds stabilise the columnar arrangement of the dimeric rings with formation of tubular assemblies. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source] Conformational analysis for some nonclassical antagonists of histamine H3 receptorINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 8 2007Ana Borota Abstract A conformational search in vacuum for a series of 1,3-substituted pyrrolidine derivatives has been performed using the AMBER, AM1, PM3, and MNDO methods. Conformational analysis of the pyrrolidine ligands suggests that these compounds could have many conformers that populate the low-energy minima on the potential energy surface (PES). The conformational space occupied by the ligands is large and, in vacuum, the rotation barriers of different flexible bonds have energies between 0.5 and thousands of kcal/mol. By optimization, most conformers have energy barriers of 0,5 kcal/mol; thus, they could interconvert easily to obtain better interactions in the receptor active site. Optimized conformers having energy barriers of >5 kcal/mol display bad geometries with very large bond lengths and deformed rings. Shapes and heights of rotation barriers obtained through COSMO,AM1 single-point calculations in water are similar to those obtained from single-point calculations in vacuum. However, in water the energy barriers are lower, allowing most conformers to convert in other low-energy conformers. The best conformers in vacuum and in water are different: the gas phase best conformer has a helical shape, while the best conformer in water has an extended shape. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007 [source] Conformational analysis of arginine in gas phase,A strategy for scanning the potential energy surface effectivelyJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 3 2008Sebastian Schlund Abstract The determination of all possible low-lying energy conformers of flexible molecules is of fundamental interest for various applications. It necessitates a reliable conformational search that is able to detect all important minimum structures and calculates the energies on an adequate level of theory. This work presents a strategy to identify low-energy conformers using arginine as an example by means of a force-field based conformational search in combination with high-level geometry optimizations (RI-MP2/TZVPP+). The methods used for various stages in the conformational search strategy are shown and various pitfalls are discussed. We can show that electronic energies calculated on a DFT level of theory with standard exchange-correlation functionals strongly underestimate the intramolecular stabilization resulting from stacked orientations of the guanidine and carbonyl moiety of arginine due to the deficiency of DFT to describe dispersion effects. In this case by usage of electron correlation methods, low energy conformers comprising stacked arrangements that are counterintuitive become favorable. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008 [source] Can a physics-based, all-atom potential find a protein's native structure among misfolded structures?JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 12 2007Abstract Recent work has shown that physics-based, all-atom energy functions (AMBER, CHARMM, OPLS-AA) and local minimization, when used in scoring, are able to discriminate among native and decoy structures. Yet, there have been only few instances reported of the successful use of physics based potentials in the actual refinement of protein models from a starting conformation to one that ends in structures, which are closer to the native state. An energy function that has a global minimum energy in the protein's native state and a good correlation between energy and native-likeness should be able to drive model structures closer to their native structure during a conformational search. Here, the possible reasons for the discrepancy between the scoring and refinement results for the case of AMBER potential are examined. When the conformational search via molecular dynamics is driven by the AMBER potential for a large set of 150 nonhomologous proteins and their associated decoys, often the native minimum does not appear to be the lowest free energy state. Ways of correcting the potential function in order to make it more suitable for protein model refinement are proposed. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2007 [source] Comparative analysis of the conformational profile of substance P using simulated annealing and molecular dynamicsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 16 2004Francesc J. Corcho Abstract The present study describes an extensive conformational search of substance P using two different computational methods. On the one hand, the peptide was studied using the iterative simulated annealing, and on the other, molecular dynamics simulations at 300 and 400 K. With the former method, the peptide was studied in vacuo with a dielectric constant of 80, whereas using the latter study the peptide was studied in a box of TIP3P water molecules. Analysis of the results obtained using both methodologies was carried out using an in-house methodology using a cluster analysis method based on information theory. Comparison of the two sampling methodologies and the different environment used in the calculations is also analyzed. Finally, the conformational motifs that are characteristic of substance P in a hydrophilic environment are presented and compared with the experimental results available in the literature. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1937,1952, 2004 [source] Systematic conformational search analysis of the SRR and RRR epimers of 7-hydroxymatairesinolJOURNAL OF PHYSICAL ORGANIC CHEMISTRY, Issue 2 2010Giovanni Li Manni Abstract An extensive and systematic conformational search was performed on the two epimers of the natural lignan 7-hydroxymatairesinol (HMR), by means of a home-made Systematic Conformational Search Analysis (SCSA) code, designed to select more and more stable conformers through sequential geometry optimization of trial structures at increasing levels of calculation theory. In the present case, the starting molecular structures were selected by the semi-empirical AM1 method and filtered , i.e. decreased in number by choosing the more stable species , on the basis of their energy calculated by the HF method and the 6-31G(d) basis set. The geometries obtained were further refined by performing density functional theory (DFT) optimizations, using the B3LYP functional and the 6-31G(d,p) basis set, both in vacuo and in ethanol solution. This procedure allowed us to isolate, at a high level of theory, three groups of epimer conformers characterized by open, semi-folded, and folded conformations. Moreover, the SCSA allowed us to describe a conformational space made-up by about 20 species for each of the two epimers. The corresponding energy content of these species was within 27,kJ,mol,1 from the absolute minimum found, both in vacuo and in ethanol solution. The conformational analysis, followed by the inspection of the stereochemistry of the two most stable conformers of both epimers, provides support in rationalizing the proposed reaction mechanism of the catalytic hydrogenolysis of the HMR to matairesinol (MAT). Copyright © 2009 John Wiley & Sons, Ltd. [source] Application of statistical potentials to protein structure refinement from low resolution ab initio modelsBIOPOLYMERS, Issue 4 2003Hui Lu Abstract Recently ab initio protein structure prediction methods have advanced sufficiently so that they often assemble the correct low resolution structure of the protein. To enhance the speed of conformational search, many ab initio prediction programs adopt a reduced protein representation. However, for drug design purposes, better quality structures are probably needed. To achieve this refinement, it is natural to use a more detailed heavy atom representation. Here, as opposed to costly implicit or explicit solvent molecular dynamics simulations, knowledge-based heavy atom pair potentials were employed. By way of illustration, we tried to improve the quality of the predicted structures obtained from the ab initio prediction program TOUCHSTONE by three methods: local constraint refinement, reduced predicted tertiary contact refinement, and statistical pair potential guided molecular dynamics. Sixty-seven predicted structures from 30 small proteins (less than 150 residues in length) representing different structural classes (,, ,, ,,/,) were examined. In 33 cases, the root mean square deviation (RMSD) from native structures improved by more than 0.3 Å; in 19 cases, the improvement was more than 0.5 Å, and sometimes as large as 1 Å. In only seven (four) cases did the refinement procedure increase the RMSD by more than 0.3 (0.5) Å. For the remaining structures, the refinement procedures changed the structures by less than 0.3 Å. While modest, the performance of the current refinement methods is better than the published refinement results obtained using standard molecular dynamics. © 2003 Wiley Periodicals, Inc. Biopolymers 70: 575,584, 2003 [source] Self-Assembled Amphotericin,B Is Probably Surrounded by Ergosterol: Bimolecular Interactions as Evidenced by Solid-State NMR and CD SpectraCHEMISTRY - A EUROPEAN JOURNAL, Issue 4 2008Yusuke Kasai Dr. Abstract Amphotericin,B (AmB) is thought to exert its pharmacological effects by forming a barrel-stave assembly with ergosterol in fungal membranes. To examine the interaction between AmB and ergosterol (Erg) or cholesterol (Cho), 13C- and 19F-labelled covalent conjugates were prepared as reported previously (N. Matsumori et,al. Chem. Biol.2004, 11, 673,679). The CD spectra of the conjugates in a membrane-bound form suggested that the distance between the heptaene moieties of the ergosterol conjugates AmB,C2,(6-F)Erg 2 and AmB,C2,Erg 3 is similar to that of AmB in ergosterol-containing membranes, but significantly larger than that of AmB in nonsterol or cholesterol-containing membranes. These observations suggest that, as is the case with ergosterol-containing membranes, the conjugated sterol moiety prevents the close contact between the heptaene moieties within the membrane that would reduce channel conductivity of the AmB assemblies. To further investigate this bimolecular interaction, we recorded the solid-state NMR spectra of conjugates 2 and AmB,C2,(6-F)Cho 4, which are composed of uniformly 13C-labelled AmB and 6-fluorinated ergosterol or cholesterol; the conjugates were expected to facilitate the estimation of distances between the fluorine and carbon atoms. By using rotor-synchronous double resonance (rotational echo double resonance of X cluster; RDX) experiments, we deduced the distance between the fluorine atom and its nearest carbon atom in the heptaene moiety of 2 to be less than 8.6,Å. This indicates that the B,ring of ergosterol comes close to the AmB polyene moiety. A conformational search of the AmB,ergosterol conjugate by using distance constraints derived from the RDX results suggested that ergosterol molecules possibly surround the AmB assembly, which is in contrast with the conventional image in which ergosterol is inserted into AmB molecules. [source] Discrimination of enantiomers of ,-amino acids by chiral derivatizing reagents from trans -1,2-diaminocyclohexane,CHIRALITY, Issue 3-4 2008Magdalena Kaik Abstract New chiral derivatizing reagents (CDAs) derived from trans -1,2-diaminocyclohexane, having an electron-deficient aromatic substituent (either an aromatic imide or 3,5-dinitrobenzamide) and rigid structure (either an amide or a urea linker), are reported. Significant shift differences of diastereotopic protons in the 1H NMR signals are observed for enantiomers of suitably protected ,-amino acids, linked to CDA by a covalent bond. A simple, general model rationalizing the observed enantiomer discrimination and based on semiempirical conformational search is presented. Chirality, 2008. © 2007 Wiley-Liss, Inc. [source] Conformationally Biased Selective Alkylation of trans -Cyclohexane-1,2-bis(sulfonamide) Assisted by Solvent-Tuned Protecting Groups: Applications to the Synthesis of a Large Optically Active Polyazamacrocycle,EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 17 2006Carmen Peña Abstract The selective alkylation of (R,R)-cyclohexane-1,2-bis(sulfonamide) with trityl bromoalkyl ethers has been studied in detail. The major formation of either mono- or dialkylated compounds clearly depends on the right combination of protecting groups and the reaction solvent. An exhaustive study suggests that this effect can be reasonably explained by the conformational preferences of the monoalkylated compounds, which also depend on the reaction medium, solvophobic effects and weak intramolecular interactions. Structural analysis by NOE measurements showed the presence of folded conformations in solution for all the tested examples. Monte Carlo conformational searches supported this proposal, showing a very good correlation between the fraction of folded species and the selectivity towards monoalkylation. Finally, tuning of the reaction conditions, leading to either extended or folded conformations of the monoalkylated synthetic intermediates, was exploited for the efficient synthesis of a large optically active polyazamacrocycle. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source] Lattice models of peptide aggregation: Evaluation of conformational search algorithmsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 15 2005Mark T. Oakley Abstract We present a series of conformational search calculations on the aggregation of short peptide fragments that form fibrils similar to those seen in many protein mis-folding diseases. The proteins were represented by a face-centered cubic lattice model with the conformational energies calculated using the Miyazawa,Jernigan potential. The searches were performed using algorithms based on the Metropolis Monte Carlo method, including simulated annealing and replica exchange. We also present the results of searches using the tabu search method, an algorithm that has been used for many optimization problems, but has rarely been used in protein conformational searches. The replica exchange algorithm consistently found more stable structures then the other algorithms, and was particularly effective for the octamers and larger systems. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 1638,1646, 2005 [source] A theoretical study of pentacyclo-undecane cage peptides of the type [Ac-X-Y-NHMe]JOURNAL OF PEPTIDE SCIENCE, Issue 2 2006Krishna Bisetty Abstract The conformational preferences of peptides of the type, Ac-X-Y-NHMe, where X and Y = Ala, cage and Pro, were studied by means of computational techniques within the framework of a molecular mechanics approach. For each of the eight peptide analogues, extensive conformational searches were carried out using molecular dynamics (MD) and simulated annealing (SA) protocols in an iterative fashion. Both results are in good agreement and complement each other. The conformational search indicates that the cage residue restricts the conformational freedom of the dipeptide considerably in comparison with the other model residues used. This study revealed that proline exhibits a greater tendency in promoting reverse-turn characteristics in comparison to the cage peptides, which show promising ,-turn characteristics. It was also found that 300,500 K is not sufficient to overcome rotational barriers for cage peptides. In all cases, the low-energy conformers have a tendency to form bent structures. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd. [source] DFT-GIAO1H NMR chemical shifts prediction for the spectral assignment and conformational analysis of the anticholinergic drugs (,)-scopolamine and (,)-hyoscyamineMAGNETIC RESONANCE IN CHEMISTRY, Issue 6 2010Marcelo A. Muñoz Abstract The relatively large chemical shift differences observed in the 1H NMR spectra of the anticholinergic drugs (,)-scopolamine 1 and (,)-hyoscyamine 2 measured in CDCl3 are explained using a combination of systematic/molecular mechanics force field (MMFF) conformational searches and gas-phase density functional theory (DFT) single point calculations, geometry optimizations and chemical shift calculations within the gauge including/invariant atomic orbital (GIAO) approximation. These calculations show that both molecules prefer a compact conformation in which the phenyl ring of the tropic ester is positioned under the tropane bicycle, clearly suggesting that the chemical shift differences are produced by the anisotropic effect of the aromatic ring. As the calculations fairly well predict these experimental differences, diastereotopic NMR signal assignments for the two studied molecules are proposed. In addition, a cursory inspection of the published 1H and 13C NMR spectra of different forms of 1 and 2 in solution reveals that most of them show these diastereotopic chemical shift differences, strongly suggesting a preference for the compact conformation quite independent of the organic or aqueous nature of the solvent. Copyright © 2010 John Wiley & Sons, Ltd. [source] Role of Environmental Factors on the Structure and Spectroscopic Response of 5,-DNA,Porphyrin Conjugates Caused by Changes in the Porphyrin,Porphyrin InteractionsCHEMISTRY - A EUROPEAN JOURNAL, Issue 44 2009Angela Mammana Dr. Abstract We have explored the utility, strength, and limitation of through-space exciton-coupled circular dichroism in determination of the secondary structure of optically active chromophoric nanoarrays using the example of end-capped porphyrin, and metalloporphyrin,oligodeoxynucleotide conjugates. We put special emphasis on the explanation of the origin and significance of the distinctive multiple bands in the CD spectra (trisignate and tetrasignate CD bands). Such CD profiles are often observed in chiral aggregates or multichromophoric arrays but have never before been studied in detail. We found that variation of temperature and ionic strength has a profound effect on the geometry of the porphyrin,DNA conjugates and thus the nature of electronic interactions. At lower temperatures and in the absence of NaCl all three 5,-DNA,porphyrin conjugates display negative bisignate CD exciton couplets of variable intensity in the Soret region resulting from through-space interaction between the electric transition dipole moments of the two end-capped porphyrins. As the temperature is raised these exciton couplets are transformed into single positive bands originating from the porphyrin,single-strand DNA interactions. At higher ionic strengths and low temperatures, multisignate CD bands are observed in the porphyrin Soret region. These CD signature bands originate from a combination of intermolecular, end-to-end porphyrin,porphyrin stacking between duplexes and porphyrin,DNA interactions. The intermolecular aggregation was confirmed by fluorescence and absorption spectroscopy and resonance light scattering. DeVoe theoretical CD calculations, in conjunction with molecular dynamics simulations and Monte Carlo conformational searches, were used to mimic the observed bisignate exciton-coupled CD spectra as well as multiple CD bands. Calculations correctly predicted the sign and shape of the experimentally observed CD spectra. These studies reveal that the exciton-coupled circular dichroism is a very useful technique for the determination of the structure of optically active arrays. [source] | ||||||||||||||||||||||