Showing papers on "Conformational isomerism published in 2003"
TL;DR: A new algorithm forSCWRL is presented that uses results from graph theory to solve the combinatorial problem encountered in the side‐chain prediction problem, and will allow for use of SCWRL in more demanding applications such as sequence design and ab initio structure prediction, as well addition of a more complex energy function and conformational flexibility, leading to increased accuracy.
Abstract: Fast and accurate side-chain conformation prediction is important for homology modeling, ab initio protein structure prediction, and protein design applications. Many methods have been presented, although only a few computer programs are publicly available. The SCWRL program is one such method and is widely used because of its speed, accuracy, and ease of use. A new algorithm for SCWRL is presented that uses results from graph theory to solve the combinatorial problem encountered in the side-chain prediction problem. In this method, side chains are represented as vertices in an undirected graph. Any two residues that have rotamers with nonzero interaction energies are considered to have an edge in the graph. The resulting graph can be partitioned into connected subgraphs with no edges between them. These subgraphs can in turn be broken into biconnected components, which are graphs that cannot be disconnected by removal of a single vertex. The combinatorial problem is reduced to finding the minimum energy of these small biconnected components and combining the results to identify the global minimum energy conformation. This algorithm is able to complete predictions on a set of 180 proteins with 34,342 side chains in <7 min of computer time. The total χ1 and χ1 + 2 dihedral angle accuracies are 82.6% and 73.7% using a simple energy function based on the backbone-dependent rotamer library and a linear repulsive steric energy. The new algorithm will allow for use of SCWRL in more demanding applications such as sequence design and ab initio structure prediction, as well addition of a more complex energy function and conformational flexibility, leading to increased accuracy.
1,069 citations
TL;DR: By probing the fluorescence lifetime of the single flavin on a photon-by-photon basis, the variation of flavin-tyrosine distance over time is observed, suggesting the existence of multiple interconverting conformers related to the fluctuating catalytic reactivity.
Abstract: Electron transfer is used as a probe for angstrom-scale structural changes in single protein molecules. In a flavin reductase, the fluorescence of flavin is quenched by a nearby tyrosine residue by means of photo-induced electron transfer. By probing the fluorescence lifetime of the single flavin on a photon-by-photon basis, we were able to observe the variation of flavin-tyrosine distance over time. We could then determine the potential of mean force between the flavin and the tyrosine, and a correlation analysis revealed conformational fluctuation at multiple time scales spanning from hundreds of microseconds to seconds. This phenomenon suggests the existence of multiple interconverting conformers related to the fluctuating catalytic reactivity.
810 citations
TL;DR: Lewis acid-mediated nucleophilic substitution reactions of substituted tetrahydropyran acetates reveal that the conformational preferences of six-membered-ring cations depend significantly upon the electronic nature of the substituent, and reinforces the idea that ground-state conformational effects need to be considered along with steric approach considerations.
Abstract: Lewis acid-mediated nucleophilic substitution reactions of substituted tetrahydropyran acetates reveal that the conformational preferences of six-membered-ring cations depend significantly upon the electronic nature of the substituent. Nucleophilic substitutions of C-3 and C-4 alkyl-substituted tetrahydropyran acetates proceeded via pseudoequatorially substituted oxocarbenium ions, as would be expected by consideration of steric effects. Substitutions of C-3 and C-4 alkoxy-substituted tetrahydropyran acetates, however, proceeded via pseudoaxially oriented oxocarbenium ions. The unusual selectivities controlled by the alkoxy groups were demonstrated for a range of other heteroatom substituents, including nitrogen, fluorine, chlorine, and bromine. It is believed that the pseudoaxial conformation is preferred in the ground state of the cation because of an electrostatic attraction between the cationic carbon center of the oxocarbenium ion and the heteroatom substituent. This analysis is supported by the observation that selectivity diminishes down the halogen series, which is inconsistent with electron donation as might be expected during anchimeric assistance. The C-2 heteroatom-substituted systems gave moderately high 1,2-cis selectivity, while small alkyl substituents showed no selectivity. Only in the case of the tert-butyl group at C-2 was high 1,2-trans selectivity observed. These studies reinforce the idea that ground-state conformational effects need to be considered along with steric approach considerations.
232 citations
TL;DR: Five conformers are distinguished among the large number of possible states of the conformational dynamic ensemble: BSA1,8‐ANS, BSA2,6‐ANS', BSAfree, B SAbis‐ans, and BSAunfolded among theLarge number of state-based ligand interactions and the relative population of each distinguishable conformer depends on the type and concentration of ligand and the temperature of the system.
Abstract: The interaction between ligands and proteins usually induces changes in protein thermal stability with modifications in the midpoint denaturation temperature, enthalpy of unfolding, and heat capacity. These modifications are due to the coupling of unfolding with binding equilibrium. Furthermore, they can be attained by changes in protein structure and conformational flexibility induced by ligand interaction. To study these effects we have used bovine serum albumin (BSA) interacting with three different anilinonaphthalene sulfonate derivatives (ANS). These ligands have different effects on protein stability, conformation, and dynamics. Protein stability was studied by differential scanning calorimetry and fluorescence spectroscopy, whereas conformational changes were detected by circular dichroism and infrared spectroscopy including kinetics of hydrogen/deuterium exchange. The order of calorimetric midpoint of denaturation was: 1,8-ANS-BSA > 2,6-ANS-BSA > free BSA >> (nondetected) bis-ANS-BSA. Both 1,8-ANS and 2,6-ANS did not substantially modify the secondary structure of BSA, whereas bis-ANS induced a distorted α-helix conformation with an increase of disordered structure. Protein flexibility followed the order: 1,8-ANS-BSA < 2,6-ANS-BSA < free BSA << bis-ANS-BSA, indicating a clear correlation between stability and conformational flexibility. The structure induced by an excess of bis-ANS to BSA is compatible with a molten globule-like state. Within the context of the binding landscape model, we have distinguished five conformers (identified by subscript): BSA1,8-ANS, BSA2,6-ANS, BSAfree, BSAbis-ANS, and BSAunfolded among the large number of possible states of the conformational dynamic ensemble. The relative population of each distinguishable conformer depends on the type and concentration of ligand and the temperature of the system.
205 citations
TL;DR: Spectral behavior with annealing indicates that the Argon matrix-isolation infrared spectra of 1-methoxy-2-(dimethylamino)ethane exhibit a band that is assigned to the most stable conformer, trans-gauche-(trans| gauche'), with an intramolecular C-H...O hydrogen bond.
Abstract: Experimental evidence for intramolecular blue-shifting C-H...O hydrogen bonding is presented. Argon matrix-isolation infrared spectra of 1-methoxy-2-(dimethylamino)ethane exhibit a band at 3016.5 cm-1. Spectral behavior with annealing indicates that this band is assigned to the most stable conformer, trans-gauche-(trans|gauche'), with an intramolecular C-H...O hydrogen bond. Density functional calculations show that this band arises from the stretching vibration of the C-H bond participating in the formation of the C-H...O hydrogen bond. The C-H bond is shortened by 0.004 A, and the C-H stretching band is blue-shifted by at least 35 cm-1 on the formation of the hydrogen bond. The (C)H...O distance is calculated as 2.38 A, which is shorter than the corresponding van der Waals separation by 0.3 A.
177 citations
TL;DR: An (15)N-enriched sample of the yeast iso-1-ferricytochrome c triple variant in an alkaline conformation was examined by NMR spectroscopy, concluding that the folded polypeptide is highly fluxional.
Abstract: An ^(15)N-enriched sample of the yeast iso-1-ferricytochrome c triple variant (Lys72Ala/Lys79Ala/Cys102Thr) in an alkaline conformation was examined by NMR spectroscopy. The mutations were planned to produce a cytochrome c with a single conformer. Despite suboptimal conditions for the collection of spectra (i.e., pH ≈ 11), NMR remains a suitable investigation technique capable of taking advantage of paramagnetism. 76% of amino acids and 49% of protons were assigned successfully. The assignment was in part achieved through standard methods, in part through the identification of groups maintaining the same conformation as in the native protein at pH 7 and, for a few other residues, through a tentative analysis of internuclear distance predictions. Lys73 was assigned as the axial ligand together with His18. In this manner, 838 meaningful NOEs for 108 amino acids, 50 backbone angle constraints, and 203 pseudocontact shifts permitted the convergence of randomly generated structures to a family of conformers with a backbone RMSD of 1.5 ± 0.2 A. Most of the native cytochrome c conformation is maintained at high pH. The NOE pattern that involves His18 clearly indicates that the proximal side of the protein, including the 20s and 40s loops, remains essentially intact. Structural differences are concentrated in the 70−80 loop, because of the replacement of Met80 by Lys73 as an axial ligand, and in the 50s helix facing that loop; as a consequence, there is increased exposure of the heme group to solvent. Based on several spectral features, we conclude that the folded polypeptide is highly fluxional.
133 citations
TL;DR: The results validate the widely used effective transition moment model for qualitative assignments of bis-porphyrin chirality and thus permit application of the exciton chiralities model.
Abstract: Chiral bis-porphyrins are currently the subject of intense interest as chiral receptors and as probes in the determination of structure and stereochemistry. To provide an improved framework for interpreting the circular dichroism (CD) spectra of bis-porphyrins, we have calculated the CD spectra of chiral bis-porphyrins from three classes: I, where porphyrins can adopt a relatively wide range of orientations relative to each other; II, porphyrins have a fixed relative orientation; III, porphyrins undergo π-stacking. The calculations primarily utilized the classical polarizability theory of DeVoe, but were supplemented by the quantum mechanical matrix method. Class I was represented by three isomers of the diester of 5α-cholestane-3,17-diol with 5-(4‘-carboxyphenyl)-10,15,20-triphenylporphin (2-αβ, 2-βα, 2-ββ). Careful analysis of the torsional degrees of freedom led to two to four minimum-energy conformers for each isomer, in each of which the phenyl−porphyrin bonds had torsional angles near 90°. Libratio...
131 citations
TL;DR: The IR absorption spectra for three conformers of the amino acid tryptophan show absorption bands that uniquely identify the conformational structure of the molecule and that are well matched by density functional theory calculations.
Abstract: We report the infrared (IR) absorption spectra of different conformational isomers of gas phase amino acid molecules in the molecular fingerprint region of 330‐1500 cm 1 . The IR absorption spectra for three conformers of the amino acid tryptophan show absorption bands that uniquely identify the conformational structure of the molecule and that are well matched by density functional theory calculations. The present observations hold great promise for future identification of conformational folding of larger molecules by means of their IR absorption characteristics.
124 citations
TL;DR: This new series of anti-influenza virus A compounds is characterized by a lipophilic part, that is the pyrrolidine ring, in addition to adamantane, that can interact with influenza A M2 protein, an ultimate future goal would be the in vitro mapping of M2 Lipophilic pocket.
119 citations
TL;DR: IR-absorption spectroscopy provides a clear identification of the reaction product and cis-AA converts back to trans-AA in a time scale of minutes at 8 K by tunneling.
Abstract: The high-energy conformer of acetic acid (cis-AA) is produced in an Ar matrix by vibrational excitation of the OH stretching overtone of the ground conformational state (trans-AA). IR-absorption spectroscopy provides a clear identification of the reaction product. cis-AA converts back to trans-AA in a time scale of minutes at 8 K by tunneling.
106 citations
TL;DR: In this paper, anharmonic vibrational ab initio calculations (CC-VSCF) for the trans and cis conformers of formic acid are reported and compared with the experimental spectra.
TL;DR: Accurate geometries, relative energies, rotational and quartic centrifugal distortion constants, dipole moments, harmonic vibrational frequencies, and infrared intensities were determined from ab initio electronic structure calculations for eighteen conformers of the neutral form of the amino acid L-proline.
Abstract: Accurate geometries, relative energies, rotational and quartic centrifugal distortion constants, dipole moments, harmonic vibrational frequencies, and infrared intensities were determined from ab initio electronic structure calculations for eighteen conformers of the neutral form of the amino acid L-proline. Only four conformers have notable population at low and moderate temperature. The second most stable conformer is only 2+/-2 kJ mol(-1) above the global minimum, while the third and fourth conformers are nearly degenerate and have an excess energy of 7+/-2 kJ mol(-1) relative to the global minimum. All four conformers have one hydrogen bond: N.HO in the lower energy pair of conformers, and NH.O in the higher energy pair of conformers. The conformer pairs differ only in their ring puckering. The relative energies of the conformers include corrections for valence electron correlation, extrapolated to the complete basis set limit, as well as core correlation and relativistic effects. Structural features of the pyrrolidine ring of proline are discussed by using the concept of pseudorotation. The accurate rotational and quartic centrifugal distortion constants as well as the vibrational frequencies and infrared intensities should aid identification and characterization of the conformers of L-proline by rotational and vibrational spectroscopy, respectively. Bonding features of L-proline, especially intramolecular hydrogen bonds, were investigated by the atoms-in-molecules (AIM) technique.
TL;DR: In this article, the Raman spectrum of liquid ethyldibromosilane, CH3CH2SiHBr2, was recorded at various temperatures between 298 and 218 K, and the spectrum of the crystal was obtained at 210 K from a sample sealed in a capillary.
Abstract: The Raman spectrum of liquid ethyldibromosilane, CH3CH2SiHBr2, was recorded at various temperatures between 298 and 218 K, and the spectrum of the crystal was obtained at 210 K from a sample sealed in a capillary. Additional spectra of the amorphous and annealed crystals, which were deposited on a copper finger cooled with boiling liquid nitrogen, were recorded. The infrared spectra were recorded of the vapor and amorphous and crystalline solid in the range 4000–50 cm−1 and mid-infrared spectra isolated at 4.8 K in argon and nitrogen matrices were also observed. These vibrational spectra show that two conformers, anti and gauche, are present in the vapor and in the liquid, but only the anti conformer remains in the crystalline solid. Three conformer pairs in the Raman spectrum of the liquid phase were used to obtain the enthalpy difference, which gave an average value of 128 ± 17 cm−1 (1.53 ± 0.2 kJ mol−1) with the anti form lower in energy. At ambient temperature it is estimated that there is 52 ± 2% of the gauche conformer present in the liquid. The optimized geometries, infrared and Raman intensities, and scaled vibrational wavenumbers for the anti and gauche conformers were obtained from ab initio MP2/6–31G(d) calculations with full electron correlation. The conformational energy difference was also obtained from ab initio MP2/6–311 + G(d,p) calculations which gave a predicted energy difference of 97 cm−1 with the anti form the conformer of lower energy. These spectroscopic and theoretical results are discussed and compared with the corresponding quantities for some similar molecules. Copyright © 2003 John Wiley & Sons, Ltd.
TL;DR: In this paper, a comparative conformational study of two related systems, methyl cyanoacetate (MCA) and cyanoacetic acid (CAA), is presented, and it is shown that both systems have two nearly isoenergetic conformers separated by similar low energy barriers (about 3 kJ mol −1 ).
TL;DR: Fender et al. as discussed by the authors used excited-state fluorescence-dip infrared spectroscopy to detect the hydride stretch infrared spectra of indole, H2O, NATA, and NATMA.
Abstract: The hydride stretch infrared spectra of indole, indole-H2O, 3-methyl indole, 3-methyl indole-H2O, the main conformer of tryptamine (TRA), two conformers of N-acetyl tryptophan amide (NATA), and three conformers of N-acetyl tryptophan methyl amide (NATMA), have been recorded in the electronically excited singlet states using excited-state fluorescence-dip infrared spectroscopy. NATA and NATMA are methyl-capped dipeptides of tryptophan that have conformational flexibility and exhibit sensitivity in their electronic spectra to the conformation of the dipeptide backbone. In the indole monomer, the indole NH stretch fundamental at the S1 origin is shifted from its ground-state value (3525 cm−1) to 3478 cm−1. The corresponding band in the indole-H2O complex appears at 3387 cm−1, shifted by a similar amount from its ground-state position (3436 cm−1). Higher vibronic levels within 1500 cm−1 of the S1 origin, which have been identified previously [B. J. Fender et al., Chem. Phys. Lett. 239, 31 (1995)] as being 1Lb...
TL;DR: Introduction of an electron-withdrawing group on the aromatic ring of N-methylacetanilide decreased the ratio of the cis conformer, and the ratio correlates well with the Hammett sigma values of the substituents.
TL;DR: In this article, the outer sphere anion reversibly displaces the central N (pyridine) unit of the pincer in a rate limiting step to form a neutral dihalo intermediate that undergoes rapid conformer interconversion.
Abstract: Interconversion of the two chiral conformations of the square planar Pd(II) CCC pincer carbene complex, 1
(η3-C,C′,C″)
(2,6-bis{[N-methyl-N′-methylene]imidazol-2-ylidene}phenyl)bromopalladium(II), and the CNC cation, 2, (η3-C,C′,N)(2,6-bis{[N-methyl-N′-methylene]imidazol-2-ylidene}pyridine)bromopalladium(II)(1+), is characterized by VT NMR spectroscopy. Combined DFT/experimental work indicates two alternative mechanisms. In the case of 1, having no counterion, and several derivatives of 2 with weakly nucleophilic counterions, the fluxional process goes in two steps via an unsymmetrical cationic 4-coordinate intermediate. In this case one carbene ring moves through the square plane before the other. In some cases for 2 with more nucleophilic counterions, such as [{CNC}PdI]I, a second lower-barrier process takes over that depends on the nature of the counterion. We propose that the outer sphere anion reversibly displaces the central N (pyridine) unit of the pincer in a rate limiting step to form a neutral dihalo intermediate that undergoes rapid conformer interconversion. This accounts for the counterion dependence and constitutes an unusual type of fluxionality that couples anion substitution at the metal with the conformational change of the ligand. A pyridine, even when present as the central element of a CNC pincer ligand, can therefore be labile even under mild conditions and reaction mechanisms involving decoordination of such group are therefore possible.
TL;DR: In this article, the 1H chemical shifts of benzaldehyde, 2-chloro-, 2-hydroxy- and 2-methoxybenzaldehyde were obtained and completely assigned in CDCl3 and DMSO solution.
Abstract: The 1H chemical shifts of benzaldehyde, 2-chloro-, 2-hydroxy- and 2-methoxybenzaldehyde, acetophenone, 2-methoxy- and 2-hydroxyacetophenone, indanone, anthraquinone, fluorenone, anthrone, -tetralone, 2,4,6-trimethylacetophenone, 9-acetylanthracene, 9-anthranaldehyde and benzosuberone were obtained and completely assigned in CDCl3 and DMSO solution. In anthrone a keto-enol tautomerism (anthrone-9-hydroxyanthracene) was observed by NMR in hydrogen bonding solvents but not chloroform. The percentage of enol is linearly dependent on the Kamlett hydrogen bonding parameter of the solvent, and not the solvent relative permittivity. The chemical shift data allowed the determination of the carbonyl substituent chemical shifts (SCS) in these molecules. These were analysed in terms of the carbonyl electric field, magnetic anisotropy and steric effects for long-range protons together with a model (CHARGE7) for the calculation of the two- and three-bond effects. The SCS of the carbonyl bond was reproduced with an asymmetric magnetic anisotropy acting at the midpoint of the carbonyl bond with values of par and perp of 6.36 and -11.88 (10-30 cm3 molecule-1) plus a steric term from the oxygen atom and the CO electric field effect. The short-range effects of the carbonyl group on the aldehyde proton were modelled using the appropriate functions in the CHARGE routine. For the 9-substituted anthracenes the Huckel calculation was modified to account for the 1H chemical shifts of the H-10 protons. This model gave a comprehensive calculation of the 1H chemical shifts of these aromatic aldehydes and ketones. For the data set of 129 chemical shifts ranging from 2.5 to 11.5 the r.m.s. error of the observed vs calculated shifts was 0.094 ppm. The CO anisotropy and oxygen shielding differ appreciably from the corresponding values for the aliphatic aldehydes and ketones but are similar to the values for the CO group of amides, illustrating the effect of conjugation on these parameters. The model was used in the conformational analysis of some related compounds. In 2-chlorobenzaldehyde the chemical shift calculations support a non-planar molecule with the aldehyde-ring dihedral angle in the trans conformer of ca 25°. In the strained seven-membered ring of benzosuberone, the model was used to test calculated geometries. The ab initio geometry at the B3LYP(6-31++G(d,p)) level gave the best agreement with the observed shifts. Copyright © 2002 John Wiley & Sons, Ltd.
TL;DR: The 1-hydroxy-1-(N-methyl)aminoethyl radical (1) represents a simple model system for hydrogen atom adducts to the amide bond in gas-phase peptide and protein ions relevant to electron capture dissociation (ECD).
Abstract: The 1-hydroxy-1-(N-methyl)aminoethyl radical (1) represents a simple model system for hydrogen atom adducts to the amide bond in gas-phase peptide and protein ions relevant to electron capture dissociation (ECD). Radical 1 was generated in the rarefied gas phase by femtosecond electron transfer to the stable cation prepared by selective O-protonation of N-methylacetamide. The main dissociations of 1 were loss of the hydroxyl hydrogen atom and the N-methyl group in a 1.7:1 ratio, as deduced from product analysis and deuterium labeling. The dissociations that occur on the 4.1 microsecond time scale are driven by large Franck−Condon effects on collisional electron transfer that deposit 93−103 kJ mol-1 in the nascent radicals. Detailed analysis of the potential energy surface for dissociations of 1 revealed several conformers and isomeric transition states for dissociations of the O−H and N−CH3 bonds. The experimental branching ratio is in quantitative agreement with RRKM calculations within the accuracy of t...
TL;DR: It is shown that, besides the steric repulsion model, the conformational energies of the compounds studied are dictated by hyperconjugative interactions involving mainly the methine hydrogen.
Abstract: Full geometry optimizations were carried out at the HF/6-31G** and B3LYP/6-31G** levels for methylcyclohexane, 2-, 3-, and 4-methyltetrahydropyran, 2-, 3-, and 4-methylpiperidine, 2-, 3-, and 4-methylthiane, 2-, 4-, and 5-methyl-1,3-dioxane, and 2-, 4-, and 5-methyl-1,3-dithiane and also for S-methyl thianium. Constrained geometry optimizations were carried out for methylcyclohexane, 2-methyl-1,3-dioxane, and the axial conformers of 2- and 3-methyltetrahydropyran and 2- and 3-methylpiperidine. The steric repulsion model, which is believed to account for the conformational energies of the cited compounds, was tested by stretching bonds and bending angles so that the axial methyl group is either forced to approach the ring gamma methylenes or get farther away from them. The calculated energies show that the energy costs of these perturbations are not dependent on the distances between the axial methyl group and the ring gamma methylenes and are not dependent on whether the methyl is axial or equatorial. It is shown that, besides the steric repulsion model, the conformational energies of the compounds studied are dictated by hyperconjugative interactions involving mainly the methine hydrogen. The C[bond]C lengths of the axial and equatorial conformers of methylcyclohexane are shown to be related to hyperconjugation.
TL;DR: The synthesis of a new class of chiral C(2)-symmetric tridentate N-donor ligands, a series of 2,5-bis(2-oxazolinylmethyl)pyrroles, was achieved in four steps suggesting that the activation barrier for conformational racemization is significantly below 10 kcal mol(-1).
Abstract: The synthesis of a new class of chiral C(2)-symmetric tridentate N-donor ligands, a series of 2,5-bis(2-oxazolinylmethyl)pyrroles, was achieved in four steps starting from the known 2,5-bis(trimethylammoniomethyl)pyrrole diiodide (1). Reaction of 1 with NaCN in dimethyl sulfoxide gave 2,5-bis(cyanomethyl)pyrrole (2) cleanly, which was then cyclized with amino alcohols to give the 2,5-bis(2-oxazolinylmethyl)pyrroles 3 a-c (3 a: bis[2-(4,4'-dimethyl-5-hydrooxazolyl)methyl]pyrrole; 3 b: (S,S)-bis[2-(4-isopropyl-4,5-dihydrooxazolyl)methyl]pyrrole; 3 c: (S,S)-bis[2-(4-tertiobutyl-4,5-dihydrooxazolyl)methyl]pyrrole). Metallation of 3 a-c with one molar equivalent of tBuLi and their subsequent reaction with a stoichiometric amount of [PdCl(2)(cod)] (cod=cyclooctadiene) gave the palladium(II) complexes 4 a-c. Whereas the arrangement of the N-donor atoms in the crystallographically characterized complex 4 a is almost ideally square planar, all three heterocycles in the ligand are twisted out of the coordination plane, leading to a chiral conformation of the complex. Attempts to freeze out these two conformers in solution at 200 K (NMR) failed, and this suggests that the activation barrier for conformational racemization is significantly below 10 kcal mol(-1). The palladium-induced shift of two double bonds as well as the porphyrinogen/porphyrin-type oxidation of the complexes 4 a-c led to the planarization of the 2,5-bis(oxazolinylmethyl)pyrrolide ligands in the palladium(II) complexes 5 a-c, 6 b, and 6 c, and to the formation of rigid chiral C(2)-symmetric systems as shown by X-ray diffraction studies. The formation of the conjugated system of double bonds in this transformation is accompanied by the emergence of an intra-ligand chromophore. This is evident in the absorption spectrum of 6 c which displays an intense band with a maximum at 485 nm attributable to an intra-ligand pi*<--pi transition and a characteristic vibrational progression of nu approximately 1350 cm(-1). Complexes 4 b and 4 c were tested in the catalytic asymmetric Michael addition of ethyl 2-cyanopropionate to methyl vinylketone (catalyst loading: 1 mol %) and were found to give maximum ee values of 43 % (4 b) and 21 % (4 c) at low conversions.
TL;DR: In this paper, the conformation dependence of UV absorption of short chain peralkylated oligosilanes is surveyed and a similar conformational effect has been found for a series of hexasilane conformers.
TL;DR: It is suggested that the methylation state of the cobalamin will influence the distribution of conformers during turnover, and steric conflicts disfavor conformers that juxtapose a methyl group on substrate with one on methylcobalamin.
Abstract: In the course of catalysis or signaling, large multimodular proteins often undergo conformational changes that reposition the modules with respect to one another. The mechanisms that direct the reorganization of modules in these proteins are of considerable importance, but distinguishing alternate conformations is a challenge. Cobalamin-dependent methionine synthase (MetH) is a 136-kDa multimodular enzyme with a cobalamin chromophore; the color of the cobalamin reflects the conformation of the protein. The enzyme contains four modules and catalyzes three different methyl transfer reactions that require different arrangements of these modules. Two of these methyl transfer reactions occur during turnover, when homocysteine is converted to methionine by using a methyl group derived from methyltetrahydrofolate. The third reaction is occasionally required for reactivation of the enzyme and uses S-adenosyl-l-methionine as the methyl donor. The absorbance properties of the cobalamin cofactor have been exploited to assign conformations of the protein and to probe the effect of ligands and mutations on the distribution of conformers. The results imply that the methylcobalamin form of MetH exists as an ensemble of interconverting conformational states. Differential binding of substrates or products alters the distribution of conformers. Furthermore, steric conflicts disfavor conformers that juxtapose a methyl group on substrate with one on methylcobalamin. These results suggest that the methylation state of the cobalamin will influence the distribution of conformers during turnover.
TL;DR: Conformational analysis using computational methods, X-ray crystallography, and NMR studies showed that the stereochemistry at C14 has a pronounced effect on the conformation of the epoxide region of epothilone.
Abstract: The syntheses of C14-methyl analogues of epothilone B and D are described. Conformational analysis using computational methods, X-ray crystallography, and NMR studies showed that the stereochemistry at C14 has a pronounced effect on the conformation of the epoxide region. Biological assays indicated significant differences in their biological activity. Substitution which stabilized conformer I retained significant biological activity. In contrast, substitution which stabilized conformer II provided analogues with no measurable cytotoxicity. The conformation−activity relationships strongly support the importance of conformer I as the bioactive conformation of the epoxide region of epothilone. The approach presented here offers a new perspective on rational design of modified biologically active polyketides.
TL;DR: A molecular mechanics docking study of (R)-norepinephrine in a model binding pocket of the beta-adrenergic receptor shows that the ligand takes a conformation close to the T(3) arrangement.
Abstract: The natural neurotransmitter (R)-norepinephrine takes the monocationic form in 93% abundance at the physiological tissue pH of 7.4. Ab initio and DFT/B3LYP calculations were performed for 12 protonated conformers of (R)-norepinephrine in the gas phase with geometry optimizations up to the MP2/6-311++G level, and with single-point calculations up to the QCISD(T) level at the HF/6-31G-optimized geometries. Four monohydrates were studied at the MP2/6-31G//HF/6-31G level. In the gas phase, the G1 conformer is the most stable with phenyl.NH(3)(+) gauche and HO(alc).NH(3)(+) gauche arrangements. A strained intramolecular hydrogen bond was found for conformers (G1 and T) with close NH(3)(+) and OH groups. Upon rotation of the NH(3)(+) group as a whole unit about the C(beta)-C(alpha) axis, a 3-fold potential was calculated with free energies for barriers of 3-12 kcal/mol at the HF/6-31G level. Only small deviations were found in MP2/6-311++G single-point calculations. A 2-fold potential was calculated for the phenyl rotation with free energies of 11-13 kcal/mol for the barriers at T = 310 K and p = 1 atm. A molecular mechanics docking study of (R)-norepinephrine in a model binding pocket of the beta-adrenergic receptor shows that the ligand takes a conformation close to the T(3) arrangement. The effect of aqueous solvation was considered by the free energy perturbation method implemented in Monte Carlo simulations. There are 4-5 strongly bound water molecules in hydrogen bonds to the conformers. Although hydration stabilizes mostly the G2 form with gauche phenyl.NH(3)(+) arrangement and a water-exposed NH(3)(+) group, the conformer population becomes T > G1 > G2, in agreement with the PMR spectroscopy measurements by Solmajer et al. (Z. Naturforsch. 1983, 38c, 758). Solvent effects reduce the free energies for barriers to 3-6 and 9-12 kcal/mol for rotations about the C(beta)-C(alpha) and the C(1)(ring)-C(beta) axes, respectively.
TL;DR: In this paper, the vertical ionization energy of l -phenylalanine was found to depend uniquely on the type of intramolecular hydrogen bonding in the neutral conformers.
TL;DR: A method to generate conformational ensembles that efficiently sample local side-chain flexibility from a single crystal structure is developed and the experimental binding mode was reproduced successfully using members of the core ensemble as the docking target, establishing the usefulness of the method in drug design.
TL;DR: In this paper, a combination of two-color resonant two-photon ionization (2C-R2PI), UV−UV hole-burning spectroscopy, and resonant ion-dip infrared spectroscopic (RIDIRS) was used to identify structural minima and to aid in the infrared spectral assignments.
Abstract: The neural hormone melatonin (N-acetyl-5-methoxytryptamine) is an indole derivative with a flexible peptide-like side chain that presents five distinct hydrogen-bonding sites for water: the carbonyl oxygen, the amide NH, the indole NH, the methoxy oxygen, and the indole π cloud. Using a combination of two-color resonant two-photon ionization (2C-R2PI), UV−UV hole-burning spectroscopy, and resonant ion-dip infrared spectroscopy (RIDIRS), the conformational preferences of melatonin upon sequential solvation with water have been examined. Density functional theory calculations are used to identify structural minima and to aid in the infrared spectral assignments. This work builds on previous results on the melatonin monomer (Florio et al. J. Am. Chem. Soc. 2002, 124, 10236), which identified five monomer conformations: three dominant trans-amide conformers and two minor cis-amide conformers. Four distinct melatonin−(water)1 complexes and two melatonin−(water)2 clusters are observed. All of these feature wa...
TL;DR: In this article, the gas-phase conformation of the model glycoside, phenyl β-D-galactopyranoside (phe-β-D -gal) was examined using a combination of resonant two-photon ionization (R2PI) and resonant ion-dip infrared spectroscopy (RIDIRS) in tandem with electronic structure theory calculations.
Abstract: The gas-phase conformation of the model glycoside, phenyl β-D-galactopyranoside (phe-β-D-gal) was examined using a combination of resonant two-photon ionization (R2PI) and resonant ion-dip infrared spectroscopy (RIDIRS) in tandem with electronic structure theory calculations. A single conformer, in which the hydroxy methyl is in a gauche+ orientation, is predominant in the free-jet expansion. This conformer is the analogue of the lowest-energy conformer found in a previous study of phenyl β-D-glucopyranoside. A minor second conformer has also been identified. Other weak bands in the R2PI spectrum have been attributed to hot bands though it is possible that other conformers are also present at low abundance. The dominant conformer identified in this work has the same (gauche+) orientation of the hydroxy methyl group as the major rotamer identified in solution by NMR spectroscopy.
TL;DR: A convergent synthesis of the E'FGH ring fragment 28 of ciguatoxin 1B, a principal toxin causing widespread seafood poisonings "ciguatera", has been accomplished through coupling between the E- ring-acetylide 9 and the H ring-aldehyde 20.
Abstract: A convergent synthesis of the E‘FGH ring fragment 28 of ciguatoxin 1B, a principal toxin causing widespread seafood poisonings “ciguatera”, has been accomplished through (i) coupling between the E‘ ring-acetylide 9 and the H ring-aldehyde 20, (ii) stereoselective F ring cyclization via an acetylene cobalt complex, (iii) conversion to a carbonyl function under high-pressure hydrogenation, and (iv) reductive hydroxyketone cyclization to construct the G ring. In the 1H NMR analysis of 28 at room temperature, a considerable broadening phenomenon was observed due to the slow conformational changes of the FG ring, as reported for natural ciguatoxin 1B. When measured in pyridine at −20 °C, the spectra of 28 exhibited a 3.5:1 mixture of two conformational isomers (UP and DOWN conformers).