Showing papers on "Conformational isomerism published in 2013"

Performance of M06, M06-2X, and M06-HF density functionals for conformationally flexible anionic clusters: M06 functionals perform better than B3LYP for a model system with dispersion and ionic hydrogen-bonding interactions.

Abstract: We present a comparative assessment of the performance of the M06 suite of density functionals (M06, M06-2X, and M06-HF) against an MP2 benchmark for calculating the relative energies and geometric structures of the Cl(-)·arginine and Br(-)·arginine halide ion-amino acid clusters. Additional results are presented for the popular B3LYP density functional. The Cl(-)·arginine and Br(-)·arginine complexes are important prototypes for the phenomenon of anion-induced zwitterion formation. Results are presented for the canonical (noncharge separated) and zwitterionic (charge separated) tautomers of the clusters, as well as the numerous conformational isomers of the clusters. We find that all of the M06 functions perform well in terms of predicting the general trends in the conformer relative energies and identifying the global minimum conformer. This is in contrast to the B3LYP functional, which performed significantly less well for the canonical tautomers of the clusters where dispersion interactions contribute more significantly to the conformer energetics. We find that the M06 functional gave the lowest mean unsigned error for the relative energies of the canonical conformers (2.10 and 2.36 kJ/mol for Br(-)·arginine and Cl(-)·arginine), while M06-2X gave the lowest mean unsigned error for the zwitterionic conformers (0.85 and 1.23 kJ/mol for Br(-)·arginine and Cl(-)·arginine), thus providing insight into the types of physical systems where each of these functionals should perform best.

Chirality sensing using stereodynamic probes with distinct electronic circular dichroism output

Abstract: Circular dichroism (CD) spectroscopy is one of the most useful techniques for the stereochemical analysis of chiral biopolymers and fine chemicals. It has become invaluable for the assignment of the absolute configuration, the study of conformational isomers, and the determination of racemization kinetics of CD active chiral compounds. Molecular interactions between a nonracemic chiral substrate and a chromophoric, CD-silent probe that is achiral or exists as a racemic mixture of rapidly interconverting enantiomeric conformations or configurations can induce a strong, characteristic chiroptical readout. A covalent or noncovalent binding event that coincides with a well-defined asymmetric induction process can effectively imprint the chiral information of the substrate on the stereodynamic sensor and thus generate intense Cotton effects in the UV region of the latter. The probe can thus function as a stereochemical reporter unit and analysis of the CD spectrum often provides accurate information about the absolute configuration and enantiomeric composition of the substrate used. In this review, recent developments in circular dichroism analysis of chiral compounds with stereodynamic probes are described and particular emphasis is given to sensor design, chiral induction processes and applications scope.

Specific Chemical Reactivities of Spatially Separated 3-Aminophenol Conformers with Cold Ca+ Ions

Abstract: Many molecules exhibit multiple rotational isomers (conformers) that interconvert thermally and are difficult to isolate. Consequently, a precise characterization of their role in chemical reactions has proven challenging. We have probed the reactivity of specific conformers by using an experimental technique based on their spatial separation in a molecular beam by electrostatic deflection. The separated conformers react with a target of Coulomb-crystallized ions in a trap. In the reaction of Ca(+) with 3-aminophenol, we find a twofold larger rate constant for the cis compared with the trans conformer (differentiated by the O-H bond orientation). This result is explained by conformer-specific differences in the long-range ion-molecule interaction potentials. Our approach demonstrates the possibility of controlling reactivity through selection of conformational states.

Cis–Trans Amide Bond Rotamers in β-Peptoids and Peptoids: Evaluation of Stereoelectronic Effects in Backbone and Side Chains

Abstract: Non-natural peptide analogs have significant potential for the development of new materials and pharmacologically active ligands. One such architecture, the β-peptoids (N-alkyl-β-alanines), has found use in a variety of biologically active compounds but has been sparsely studied with respect to folding propensity. Thus, we here report an investigation of the effect of structural variations on the cis–trans amide bond rotamer equilibria in a selection of monomer model systems. In addition to various side chain effects, which correlated well with previous studies of α-peptoids, we present the synthesis and investigation of cis–trans isomerism in the first examples of peptoids and β-peptoids containing thioamide bonds as well as trifluoroacetylated peptoids and β-peptoids. These systems revealed an increase in the preference for cis-amides as compared to their parent compounds and thus provide novel strategies for affecting the folding of peptoid constructs. By using NMR spectroscopy, X-ray crystallographic ...

Accurate structure, thermodynamic and spectroscopic parameters from CC and CC/DFT schemes: the challenge of the conformational equilibrium in glycine

Abstract: The structures, relative stabilities, and infrared spectra of the six low-energy conformers of glycine have been characterized using a state-of-the-art quantum-mechanical approach allowing the bond distances, conformational enthalpies and vibrational frequencies to be determined well within the chemical accuracy. Transition state structures governing interconversion among the different energy minima have also been characterized. In detail, the gas-phase thermodynamic properties (at 15 K and 410 K) of the glycine conformers considered have been obtained with a 1 kJ mol−1 accuracy, and it has been shown that the employment of DFT geometries usually reduces such accuracy by at most 0.1 kJ mol−1. Regarding molecular structures, the use of two different composite schemes allowed us to further confirm the suitability of a rather cost-effective approach and provide geometrical parameters with an overall accuracy better than 0.002 A for distances and 1 degree for angles. Thanks to a hybrid CC/DFT approach, the infrared spectra of all conformers considered and of several deuterated isotopologues have been reproduced (when experimental data were available) or predicted with an accuracy of 10 cm−1. Finally, the joint thermodynamic and spectroscopic investigation allowed us to shed some light on the possible observation of elusive conformers. On the whole, the high accuracy of the computational results allows us to draw a fully consistent interpretation of the available experimental data and to obtain a more complete characterization of the potential energy surface of glycine.

Characterization of amide bond conformers for a novel heterocyclic template of N-acylhydrazone derivatives.

Abstract: Herein we describe NMR experiments and structural modifications of 4-methyl-2-phenylpyrimidine-N-acylhydrazone compounds (aryl-NAH) in order to discover if duplication of some signals in their ¹H- and ¹³C-NMR spectra was related to a mixture of imine double bond stereoisomers (E/Z) or CO-NH bond conformers (syn and anti-periplanar). NMR data from NOEdiff, 2D-NOESY and ¹H-NMR spectra at different temperatures, and also the synthesis of isopropylidene hydrazone revealed the nature of duplicated signals of a 4-methyl-2-phenylpyrimidine-N-acylhydrazone derivative as a mixture of two conformers in solution. Further we investigated the stereoelectronic influence of substituents at the ortho position on the pyrimidine ring with respect to the carbonyl group, as well as the electronic effects of pyrimidine by changing it to phenyl. The conformer equilibrium was attributed to the decoplanarization of the aromatic ring and carbonyl group (generated by an ortho-alkyl group) and/or the electron withdrawing character of the pyrimidine ring. Both effects increased the rotational barrier of the C-N amide bond, as verified by the DG(≠) values calculated from dynamic NMR. As far as we know, it is the first description of aryl-NAH compounds presenting two CO-NH bond- related conformations.

Glycine conformers: a never-ending story?

Abstract: The structure and vibrational spectra of a marginally stable conformer of glycine (usually referred to as VIp or ttc) recently detected in low-temperature matrices have been characterized by a state-of-the-art computational approach allowing an overall quality for bond distances, rotational constants, conformational enthalpies and vibrational frequencies well within the chemical accuracy. The high accuracy of the computational results allows us to draw a fully consistent interpretation of the available experimental data and to obtain a more complete characterization of an elusive glycine conformer.

The Role of Arene–Arene Interactions in the Folding of ortho-Phenylenes

Abstract: The ortho-phenylenes are a simple class of helical oligomers and representative of the broader class of sterically congested polyphenylenes. Recent work has shown that o-phenylenes fold into well-defined helical conformations (in solution and, typically, in the solid state); however, the specific causes of this folding behavior have not been determined. Here, we report the effect of substituents on the conformational distributions of a series of o-phenylene hexamers. These experiments are complemented by dispersion-corrected DFT calculations on model oligomers (B97-D/TZV(2d,2p)). The results are consistent with a deterministic role for offset arene–arene stacking interactions on the folding behavior. On the basis of the experimental and computational results, we propose a model for o-phenylene folding with two simple rules. (1) Conformers are forbidden if they include a particular sequence of biaryl torsional states that causes excessive steric strain. These “ABA” states correspond to consecutive dihedral...

β₂-adrenergic receptor activation by agonists studied with ¹⁹F NMR spectroscopy.

Abstract: G-protein-coupled receptors (GPCRs) recognize a wide array of orthosteric ligands in their binding site on the periplasmic cell membrane surface, initiating signal transmission through the cellular membrane to cytoplasmic partner proteins. Crystal structures of several human GPCRs in complexes with antagonists and agonists provide insights into activation-related structural rearrangements,[1] and fluorescence spectroscopy experiments indicated activation-related conformational changes in detergent-solubilized receptors.[2] 19F-NMR spectroscopy and site-specific mutagenesis, as applied previously with mammalian rhodopsin,[3] more recently revealed an equilibrium between an activated state A and an inactive state I in the β2-adrenergic receptor (β2AR).[4] This communication now presents thermodynamic and kinetic data for this conformational equilibrium in β2AR. In our earlier experiments,[4] the β2AR complexes were reconstituted in mixed micelles of n-dodecyl-β-D-maltoside (DDM) and cholesteryl hemisuccinate (CHS), with DDM:CHS = 5:1, and 19F-labels were introduced by conjugation of 2,2,2-trifluoroethanethiol (TET) with cysteines near the cytoplasmic ends of the helices VI (Cys265) and VII (Cys327), and at the C-terminus (Cys341). Ligand binding assays showed that the labeled proteins retained the biological activity.[4] Sequence-specific 19F-NMR assignments were based on comparison of β2AR variants with single-residue TET-labeling, and the signal I was assigned from its high intensity in the apo-form of β2AR and its complexes with inverse agonists.[4] Observation of the TET labels in β2AR-complexes with different pharmacological ligands then enabled to distinguish between the activation of two different signaling pathways.[4] A first extension of the previous work was to analyze the temperature dependence of the 1D 19F-NMR spectra of β2AR (TETC265, C327S, C341A) and β2AR (C265A, TETC327, C341A) in terms of the thermodynamic parameters that characterize the conformational equilibrium between the states A and I. This analysis was focused on complexes with agonists, i.e., norepinephrine and formoterol, since for the complexes with antagonists or inverse agonists the amplitude of the signal A is near the noise level and its volume cannot reliably be quantified. Based on the observation that the temperature dependence over the range 280 K to 310 K of the NMR spectra recorded with the agonist complexes was reversible, the relative populations of the conformations represented by the signals A and I, pA and pI, were determined by fits to a double-Lorentzian function (Figure 1), yielding an apparent equilibrium constant, K = pI/ pA. ln K was found to depend linearly on the inverse of the temperature, T (Figure 2), which is in agreement with the van’t Hoff relationship between K, the molar enthalpy difference, ΔH0, and the molar entropy difference, ΔS0.[5] lnK=−(ΔH0−TS0)/RT, (1) where R is the gas constant. ΔH0 values near 40 kJ/mol were obtained for both labeling sites at Cys265 and Cys327, and for both agonists used (Table 1), suggesting that the structural differences between the states A and I observed in the 19F-NMR spectra (Figure 1) represent more extensive conformational rearrangements than, for example, reorientation of a single amino acid side chain. For the different systems in Table 1 the Gibbs free energy, ΔG0 = −ln(K)RT, is between 0 and 3 kJ/mol, which shows that the entropy and enthalpy terms (Table 1) nearly cancel each other. This observation is in line with the widely observed entropy–enthalpy compensation in biological systems.[6] Figure 1 1D 19F-NMR spectra at 280 K, 298 K and 310 K of the complexes with the partial agonist norepinephrine (upper row) and the full agonist formoterol (lower row) of β2AR(TETC265, C327S, C341A) and β2AR(C265A, TETC327, C341A) in mixed micelles of ... Figure 2 van’t Hoff plots for the interconversion between the active state (A) and the inactive state (I) of β2AR(TETC265, C327S, C341A) and β2AR(C265A, TETC327, C341A) in the complexes with norepinephrine and formoterol. The apparent equilibrium constants, ... Table 1 Molar enthalpy differences, ΔH0, and molar entropy differences, ΔS0, for the interconversion between the activated and inactive states of the formoterol and norepinephrine complexes of β2AR (TETC265, C327S, C341A) and β ... To investigate the exchange rates between the states A and I within the framework of a 2-state model, where k1 and k−1 are the forward and reverse rate constants, A⇄k−1k1I, (2) we used 2D 19F–19F exchange spectroscopy (EXSY)[7] and 1D 19F saturation transfer NMR experiments.[8] The overall exchange rate constant, kex, is given by kex=k1+k−1=k1/pI=k−1/pA, (3) where pA and pI are the relative populations of the states A and I. The observation of two distinct signals A and I in the 19F-NMR spectra of β2AR (Figure 1) showed that the conformational exchange is slow on the 19F-NMR chemical shift time scale, so that kex satisfies the inequality, kex≪Δω2pApI, (4) where Δω is the chemical shift between I and A in rad/sec.[9] For TET-labeled Cys265 and Cys327 the Δω values are 2×103 rad/sec and 4×103 rad/sec, respectively, and pA = 1−pI is between 0.2 and 0.9.[4] An upper limit of kex ≤ 103 s−1 was thus previously established, and additional support for this limit was obtained from experiments with paramagnetic shift reagents.[4] Here, 2D [19F,19F]-EXSY experiments with a TET β2AR–isoproterenol complex were performed with mixing times of 300 and 600 ms. For kex values of 10 s−1 or larger, 2D [19F,19F]-cross-peaks between the signals A and I are predicted to be of similar size as the diagonal peaks in these experiments (Figure 3c). The absence of [19F,19F]-cross-peaks (Figure 3) then enabled us to establish a new upper limit of kex < 10 s−1 at 280 K. 19F-NMR saturation-transfer experiments with apo- β2AR(C265A, TETC327, C341A) at 280 K further indicated that the exchange rate is significantly slower than 10 s−1. Considering the spectral overlap of the two signals (Figure 4), we applied selective off-resonance continuous wave (cw) pre-irradiation in these experiments (Figure 4), and analyzed the resulting intensity variations of the signals A and I with model simulations based on the Bloch equations for two-site exchange (Equations (5) to (10) in the Appendix).[10] The longitudinal and transverse spin relaxation times, T1 and T2, used in these model computations were determined with an inversion–recovery experiment (see the Experimental Section), and from the line shapes of the signals in the 1D 19F-NMR spectrum (top trace in Figure 4), respectively. Comparison of the experimental data with the simulations (Figure 5) showed that the observed decay of the signal I was due to direct saturation by the off-resonance irradiation, and that there was no measureable contribution due to coherence transfer from signal A to signal I by conformational exchange (Figure 5). Figure 3 2D [19F,19F]-EXSY experiments with the isoproterenol complex of wild type β2AR (TETC265, TETC327, TETC341) in mixed micelles of DDM and CHS 5:1. (a) Contour plot. At the top the chemical shifts of five previously assigned peaks[4] are indicated, ... Figure 4 1D 19F-NMR saturation transfer experiments with apo-β2AR(C265A, TETC327, C341A) in mixed micelles of DDM and CHS 5:1 used to measure the exchange rate between activated state (A) and inactive state (I) of β2AR. Top trace: 1D 19F-NMR spectrum, ... Figure 5 Model simulations of the attenuation of the intensity of signal I in the NMR spectra of Figure 4 by off-resonance continuous wave (cw) pre-irradiation at the chemical shifts i to v. The relative peak volumes of the signal I in 1D 19F-NMR saturation transfer experiments, ... In conclusion, this paper used TET 19F-NMR probes attached to three cysteine residues near the cytoplasmic surface to determine thermodynamic and kinetic parameters for the equilibrium between an active state, A, and an inactive state, I, of β2AR, which both represent an ensemble of rapidly interconverting conformers. Slow exchange, on the TET 19F-NMR chemical shift timescale, between the states I and A enabled a quantitative characterization of this rate process. Large values for ΔH0 (Table 1) and an exchange rate slower than 10 S−1 (Figures 3–5) indicate that the interconversion entails major structural rearrangements, which likely involve polypeptide backbone segments.[11] Furthermore, the near-identical values of ΔH0 for different ligands bound to the receptor (Table 1) indicate that the equilibrium between the two states is an intrinsic property of the receptor, so that binding of different orthosteric ligands, allosteric effectors, and possibly of cytoplasmic partner proteins would result in shifts of this pre-existing equilibrium. Comparison with recent related studies of β2AR in DDM micelles shows that TET-labeling provides different information from NMR experiments using either a different 19F-label, 3-bromo-1,1,1-trifluoroacetone (BTFA), on Cys 265[12] or 13C-labeled Met 82,[13] which both provided evidence for two or multiple states of β2AR in fast exchange on the respective chemical shift time scales. Results obtained by combining BTFA-labeling of Cys 265 with the use of the detergent maltose-neopentyl-glycol (MNG-3) were interpreted in terms of slow exchange between at least three states of β2AR.[12] Different experimental approaches thus appear to provide complementary information on the β2AR system, and one can look forward to continued studies of the dynamics of GPCRs with a variety of different reporter groups, including investigations of possible modulation of the protein conformational equilibria by allosteric effectors.

Sulfur‐Bridged BODIPY DYEmers

Abstract: Reactions of BODIPY monomers with sulfur nucleophiles and electrophiles result in the formation of new BODIPY dimers. Mono- and disulfur bridges are established, and the new dyestuff molecules were studied with respect to their structural, optical, and electrochemical properties. X-ray diffraction analyses reveal individual angulated orientations of the BODIPY subunits in all cases. DFT calculations provide solution conformers of the DYEmers which deviate in a specific manner from the crystallographic results. Clear exciton-like splittings are observed in the absorption spectra, with maxima at up to 628 nm, in combination with the expected weak fluorescence in polar solvents. A strong communication between the BODIPY subunits was detected by cyclic voltammetry, where two separated one-electron oxidation and reduction waves with peak-to-peak potential differences of 120–400 mV are observed. The qualitative applicability of the exciton model by Kasha for the interpretation of the absorption spectral shape with respect to the conformational state, subunit orientation and distance, and conjugation through the different sulfur bridges, is discussed in detail for the new BODIPY derivatives. This work is part of our concept of DYEmers, where the covalent oligomerisation of BODIPY-type dye molecules with close distances is leading to new functional dyes with predictable properties.

Near-infrared laser induced conformational change of alanine in low-temperature matrixes and the tunneling lifetime of its conformer VI.

Abstract: The near- and mid-IR spectra of α-alanine isolated in low-temperature Ar, Kr, and N2 matrixes were measured. Production of the short-lived conformer VI at the expense of the predominant conformer I...

The intrinsic conformational features of amino acids from a protein coil library and their applications in force field development

Abstract: The local conformational (ϕ, ψ, χ) preferences of amino acid residues remain an active research area, which are important for the development of protein force fields. In this perspective article, we first summarize spectroscopic studies of alanine-based short peptides in aqueous solution. While most studies indicate a preference for the PII conformation in the unfolded state over α and β conformations, significant variations are also observed. A statistical analysis from various coil libraries of high-resolution protein structures is then summarized, which gives a more coherent view of the local conformational features. The ϕ, ψ, χ distributions of the 20 amino acids have been obtained from a protein coil library, considering both backbone and side-chain conformational preferences. The intrinsic side-chain χ1 rotamer preference and χ1-dependent Ramachandran plot can be generally understood by combining the interaction of the side-chain Cγ/Oγ atom with two neighboring backbone peptide groups. Current all-atom force fields such as AMBER ff99sb-ILDN, ff03 and OPLS-AA/L do not reproduce these distributions well. A method has been developed by combining the ϕ, ψ plot of alanine with the influence of side-chain χ1 rotamers to derive the local conformational features of various amino acids. It has been further applied to improve the OPLS-AA force field. The modified force field (OPLS-AA/C) reproduces experimental 3J coupling constants for various short peptides quite well. It also better reproduces the temperature-dependence of the helix–coil transition for alanine-based peptides. The new force field can fold a series of peptides and proteins with various secondary structures to their experimental structures. MD simulations of several globular proteins using the improved force field give significantly less deviation (RMSD) to experimental structures. The results indicate that the local conformational features from coil libraries are valuable for the development of balanced protein force fields.

Conformational relaxation of S-(+)-carvone and R-(+)-limonene studied by microwave Fourier transform spectroscopy and quantum chemical calculations

Abstract: S-(+)-carvone (C10H14O, 5-isopropenyl-2-methylcyclohex-2-en-1-one) and R-(+)-limonene (C10H16, 4-isopropenyl-1-methylcyclohexene) have been characterized in the gas phase using a Fourier transform microwave spectrometer coupled to a supersonic molecular beam. Two conformers—with the isopropenyl group in the equatorial position—have been detected for each compound and described by a set of molecular parameters including the principal rotational constants and the quartic centrifugal distortion parameters. Quantum chemical calculations indicate that a third conformer might not be observed due to relaxation processes in the jet. The gas phase results are compared with the liquid phase IR-Raman-VCD spectra.

Topology switching in [32]heptaphyrins controlled by solvent, protonation, and meso substituents.

Abstract: The switching of topology between "figure-eight", Mobius, and untwisted conformations in [32]heptaphyrins(1.1.1.1.1.1.1) has been investigated by using density functional theory calculations. Such a change is achieved by variation of one internal dihedral angle and, if properly controlled, can provide access to molecular switches with unique optical and magnetic properties. In this work, we have explored different conformational control methods, such as solvent, protonation and meso substituents. Despite its antiaromatic character, most of the [32]heptaphyrins (R=H, CH(3), CF(3), Ph, C(6)F(5)) adopt a figure-eight conformation in the neutral state, owing to their more-effective hydrogen-bonding interactions. The aromatic Mobius topology is only preferred with dichlorophenyl groups, which minimize the steric hindrance that arises from the bulky chlorine atoms. The conformational equilibrium is sensitive to the solvent, so polar solvents, such as DMSO, further stabilize the Mobius conformation. Protonation induces a conformational change into the Mobius topology, irrespective of the meso-aryl groups. In the triprotonated species, the conformational switch is blocked and a non-twisted conformer becomes much more stable than the figure-eight conformation. We have shown that the relative energies of the protonated [32]heptaphyrins are dominated by aromaticity. Importantly, this topology switching induces a dramatic change in the magnetic properties and reactivity of the macrocycles, as revealed by several energetic, magnetic, structural, and reactivity indices of aromaticity.

Near-IR laser generation of a high-energy conformer of L-alanine and the mechanism of its decay in a low-temperature nitrogen matrix.

Abstract: Monomers of L-alanine (ALA) were isolated in cryogenic nitrogen matrices at 14 K. Two conformers were identified for the compound trapped from the gas-phase into the solid nitrogen environment. The potential energy surface (PES) of ALA was theoretically calculated at the MP2 and QCISD levels. Twelve minima were located on this PES. Seven low-energy conformers fall within the 0–10 kJ mol−1 range and should be appreciably populated in the equilibrium gas phase prior to deposition. Observation of only two forms in the matrices is explained in terms of calculated barriers to conformational rearrangements. All conformers with the O=C−O−H moiety in the cis orientation are separated by low barriers and collapse to the most stable form I during deposition of the matrix onto the low-temperature substrate. The second observed form II has the O=C−O−H group in the trans orientation. The remaining trans forms have very high relative energies (between 24 and 30 kJ mol−1) and are not populated. The high-energy trans form VI, that differs from I only by rotation of the OH group, was found to be separated from other conformers by barriers that are high enough to open a perspective for its stabilization in a matrix. The form VI was photoproduced in situ by narrow-band near-infrared irradiation of the samples at 6935–6910 cm−1, where the first overtone of the OH stretching vibration in form I appears. The photogenerated form VI decays in N2 matrices back to conformer I with a characteristic decay time of ∼15 min. The mechanism of the VI → I relaxation is rationalized in terms of the proton tunneling.

Dispersion‐Driven Conformational Isomerism in σ‐Bonded Dimers of Larger Acenes

Abstract: known to be a problem in those applications, and it has been investigated in some detail. As the larger acenes have become experimentally accessible, studying their properties seems worthwhile. From a theoretical point of view, the butterfly structure of the dimers with four intramolecularly pstacked acene sub-systems makes them very interesting and challenging molecules. It was recently reported that a tert-butyl substituted hexaphenylethane derivative displays a rare case of bond length isomerism, which is mainly caused by attractive London dispersion interactions between the bulky substituents. Herein, we investigate possible extensions of this concept of dispersion-driven isomerism. It is shown that covalently bonded dimers of larger acenes can display an unusual conformational isomerism that is driven by strong intramolecular dispersion interactions between the p-stacked acene subunits. The two postulated structures are the common open form and a bent conformer with a p-stacked alignment of bent acene subunits (Figure 1). The stacked form was already found by Zade et al. in their theoretical investigation of the dimerization reaction of heptacene, and was described as an intermediate. The acene dimers considered here are certainly not the ideal molecules for making functional systems (such as switches, parts of molecular motors) but should merely serve as model compounds for the basic process of dispersion-driven isomerism. It can be expected that similar double-minimum-shaped potential energy curves (PECs) to those reported here are inherent in other (supramolecular) p-systems. With increasing number of annulated rings, the mostly additive dispersion interaction of the acene subunits should at some point overcome the ring bending and Pauli repulsion energy, and the stacked conformer should become more stable. This is related to the folding of long n-alkane chains, where the folded structure is energetically favored after a distinct turning point, as recently shown by L ttschwager et al. Herein, we present PECs for the symmetric opening of the stacked to the open conformer for the heptacene and nonacene dimers. Opposed to the dimerization reaction itself, this conformational process does not involve any orbital crossing and can thus be investigated using single-reference quantum chemical methods. For the heptacene dimer, accurate wavefunction-based calculations were carried out, employing the efficient LPNO-CEPA implementation by Neese and co-workers. The coupled electron pair approach (CEPA, version “1”) was already shown to yield accurate results for general thermochemistry and non-covalent interactions. Combined with the localized pair natural orbitals (LPNO) approximation, significant computational speedups can be achieved without much loss of accuracy. Application of somewhat simplified computational methods is mandatory as the heptacene dimer comprises 96 atoms, which is rather challenging size for a correlated wavefunction treatment. Concerning the here relevant non-covalent interactions, the LPNO-CEPA reference method was already applied to protein–ligand interaction energies with good success. For comparison, two conceptually different flavors of dispersion corrected density functional theory (DFT) are employed, the well-established atom-pairwise DFT-D3 and a non-local Scheme 1. Prototypical dimerization reaction of larger acenes with an odd number of benzene rings. Figure 1. Stacked (left) and open (right) forms that were used for the construction of the potential energy curve of the heptacene dimer and analogously for the nonacene dimer. The atoms marked in black were kept fixed while relaxing all remaining degrees of freedom. The arrow indicates the distance variable (reaction coordinate) used throughout.

Structural Factors Controlling the Spin–Spin Exchange Coupling: EPR Spectroscopic Studies of Highly Asymmetric Trityl–Nitroxide Biradicals

Abstract: Highly asymmetric exchange-coupled biradicals, e.g., the trityl–nitroxides (TNs), possess particular magnetic properties that have opened new possibilities for their application in biophysical, physicochemical, and biological studies. In the present work, we investigated the effect of the linker length on the spin–spin coupling interaction (J) in TN biradicals using the newly synthesized biradicals CT02-GT, CT02-AT, CT02-VT, and CT02-PPT as well as the previously reported biradicals TNN14 and TN1. The results show that the magnitude of J can be easily tuned from ∼4 G (conformer 1 in CT02-PPT) to >1200 G (in TNN14) by varying the linker separating the two radical moieties and changing the temperature. Computer simulations of EPR spectra were carried out to estimate J values of the TN biradicals directly. In addition to the spin–spin coupling interaction of TN biradicals, their g, hyperfine-splitting, and zero-field-splitting interactions were explored at low temperature (220 K). Our present study clearly s...

Conformational sensitivity in photoelectron circular dichroism of 3-methylcyclopentanone.

Abstract: A study of (R)-3-methylcyclopentanone [(R)-3-MCP] by photoelectron spectroscopy and photoelectron circular dichroism (PECD) is presented. The synchrotron radiation gas-phase photoelectron spectra of (R)-3-MCP were measured and are discussed on the basis of different theoretical methodologies. The experimental dichroism of (R)-3-MCP for selected deconvoluted valence states and for the carbonyl carbon 1s core state are reported and reproduced well by calculated dispersions generated by considering the contributions of two different conformers. The theoretical dichroic parameters are calculated by employing a multicentre basis set of B-spline functions and a Kohn-Sham Hamiltonian. Temperature-dependent PECD studies of the HOMO state and the carbonyl carbon 1s core level allowed the separation of the contributions of each conformer by photoelectron dichroism. This new approach clearly shows how the PECD methodology is sensitive to conformational and structural changes of unoriented (R)-3-MCP in the gas phase, opening up new perspectives in the characterisation of chiral molecular systems.

Towards a first-principles model of Fermi resonance in the alkyl CH stretch region: application to 1,2-diphenylethane and 2,2,2-paracyclophane.

Abstract: The spectroscopy of two flexible hydrocarbons, 1,2-diphenylethane (DPE) and 2,2,2-paracyclophane (TCP) is presented, and a predictive theoretical model for describing the alkyl CH stretch region of these hydrocarbons is developed. Ultraviolet hole-burning spectroscopy identified two isomers of DPE and a single conformation of TCP present in the supersonic jet expansion. Through the analysis of the ground state low-frequency vibronic spectroscopy obtained by dispersed fluorescence, conformational assignments were made for both DPE and TCP. The two isomers of DPE were found to retain the low energy structures of butane, being present in both the gauche and anti structures. TCP forms a C 2 symmetric structure, differing from the predicted lower energy C 3 conformation by the symmetry of the ethano bridges (−CH2CH2−) linking the phenyl substituents. Resonant ion-dip infrared spectroscopy is used to record single-conformation IR spectra of the two conformers of DPE and the single conformer of TCP in the alkyl CH stretch region and in the mid-IR that covers the CH bend fundamentals. A local mode Hamiltonian that incorporates cubic stretch-bend coupling is developed. Its parameters are obtained from density functional theory methods. Full dimensional calculations are compared to those that use reduced dimensional Hamiltonians in which anharmonic CH stretches and scissor modes are Fermi coupled. Excellent agreement is found. Scale factors of select terms in the reduced dimensional Hamiltonian are determined by fitting the theoretical Hamiltonian to the anti-DPE spectrum. The scaled Hamiltonian is then used to predict successfully structures for the remaining lower symmetry experimentally determined spectra in the alkyl CH stretch region.

Six pyranoside forms of free 2-deoxy-D-ribose.

Abstract: Carbohydrates are one of the most versatile biochemical building blocks, widely acting in energetic, structural, or recognition processes. The interpretation of the biological activity of saccharides is based on the structure and relative stability of their conformers. One of the obstacles to resolving the basic structure issues arises from their ability to form strong intermolecular hydrogen bonds with polar solvents, which in turn can result in conformational changes. A clear picture of the conformational panorama of isolated 2-deoxyd-ribose has been revealed using Fourier-transform microwave spectroscopy in conjunction with a UV ultrafast laser ablation source. Additionally, the availability of rotational data has been the main bottle-neck for examining the presence of these building blocks in interstellar space, so these studies could also be useful to the astrochemistry community. 2-Deoxy-d-ribose (2DR, C5H10O4; Figure 1a) is an important naturally occurring monosaccharide, present in nucleotides, which are the building blocks for DNA. In DNA, 2DR is present in the furanose (five-membered) ring form, whereas free in aqueous solution it cyclizes into fiveor six-membered rings, with the latter—the pyranoid form—being dominant. By closing the chain into a six-membered ring, the C1 carbon atom is converted into an asymmetric center, yielding two possible stereochemical a and b anomeric species (Figure 1b). In aqueous solution, 2DR primarily exists as a mixture of nearly equal amounts of a and b pyranose forms, present in their low-energy chair conformations, C1 and C4 (Figure 1c). [4] Such configurations are connected through ring inversion, thus establishing the axial or equatorial position of the OH group for each conformer. In addition, the monossacharides exhibit an unusual preferential stabilization of pyranose rings containing an axial OH group at the C1 carbon over the equatorial orientation, widely known as the anomeric effect, although its physical origin remains controversial. Nevertheless, structural analysis of 2DRmust take into consideration the intramolecular hydrogen bonding between adjacent OH groups. The formation of hydrogenbond networks reinforces their stability owing to hydrogenbond cooperativity effects. Such networks are fundamental to the molecular recognition of carbohydrates. By dissecting all these factors we can determine the most stable conformers of 2DR and the relative arrangement of the different hydroxy groups under isolated conditions, such as in the gas phase. In vacuo theoretical calculations, carried out on a-/bpyranoses, a-/b-furanoses, and open-chain conformations, predict 15 furanose and pyranose forms (Figure 1d, Table 1) in an energy window of 12 kJmol 1 above the predicted cc-apyr C1 global minimum. The notation used to label the different conformers include the symbols a and b to denote the anomer type, C1 and C4 to denote the pyranose chair form, C2-endo or C3-endo to denote the furanose envelope forms, and “c” or “cc” to indicate a clockwise or counterclockwise configuration of the adjacent OH bonds, respectively. A number is added to provide theMP2 energy ordering within the same family. To validate the predicted conformational behavior, comparison with precise experimental data of 2DR is needed. Previous experiments to determine the conformation of monosaccharides were based on X-ray and NMR measurements. However, these data are influenced by environmental effects associated with the solvent or crystal lattice. Recently, an IR spectrum of 2DR in an inert matrix in

Conformational equilibria in carboxylic acid bimolecules: a rotational study of acrylic acid-formic acid.

Abstract: The bimolecule acrylic acid–formic acid has been investigated by pulsed jet Fourier transform microwave spectroscopy. The complex adopts two different conformational shapes, according to the cis or trans forms of the acrylic acid moiety. The measurements have been extended to four deuterated and to four 13C (natural abundance) species, and their combinations, for each conformer. These data allowed us to determine the carbon skeleton structures and to size quantitatively the structural effect caused by the OH → OD isotopic substitutions (the Ubbelohde effect).

Conformational analysis and synthetic approaches to polydentate perhydro-diazepine ligands for the complexation of gallium(III)

Abstract: Synthetic approaches are reported to polydentate ligands based on 6-phenyl-6-amino-perhydro-1,4-diazepine. The synthetic route devised averts ring-opening reactions, allowing the exocyclic N-substituent to be introduced separately and involves a nitro-Mannich condensation, prior to chemoselective RANEY® nickel reduction. Comparison of the solid-state structures of four synthetic intermediates reveals that the seven-membered ring adopts a preferred twist-chair conformer in the solid state. Solution state NMR experiments highlight a conformational preference for the bulky aryl groups to adopt an equatorial site, pre-disposing the ligand to metal binding, by adoption of a conformation that creates a facial array of the ligand nitrogen atoms. This ligand conformation averts the formation of less stable metal complexes with differing ligation modes, notably in the binding of Ga(3+) to related ligands, where a C-methyl substituent replaces the phenyl group at the quaternary centre.

Intramolecular Interactions in 2-Aminoethanol and 3-Aminopropanol

Abstract: Gas-phase vibrational spectra of 2-aminoethanol and 3-aminopropanol were recorded up to the third OH-stretching overtone using Fourier transform infrared spectroscopy, cavity ringdown spectroscopy, and intracavity laser photoacoustic spectroscopy. The experimental investigation was supplemented by local mode calculations, and the intramolecular interactions were investigated using atoms in molecules (AIM) and noncovalent interactions (NCI) theories. All calculations were performed at the CCSD(T)-F12a/VDZ-F12 level of theory. For both compounds the most abundant conformer has a structure that allows for hydrogen bond interaction from the OH group to the N atom of the amino group (OH–N). The spectra show signals from both hydrogen bonded and free OH stretches, implying the presence of several conformers. We observe hydrogen-bond-like interactions in both compounds. The red shift of the bonded OH-stretching frequency and intensity enhancement of the fundamental transition suggest that the hydrogen bond inter...

Conformations of D-xylose: the pivotal role of the intramolecular hydrogen-bonding.

Abstract: Crystalline samples of D-xylose have been vaporized by laser ablation and probed in the gas phase using Fourier transform microwave spectroscopy. The rotational spectrum revealed the existence of two α-D-xylopyranose conformers stabilized by the anomeric effect and cooperative hydrogen bond networks. The experiment spectroscopically tracked fine structural changes upon clockwise and counterclockwise arrangements of the OH groups in the observed conformers. The five monosubstituted 13C species of the most abundant conformer cc-α-4C1 have also been observed in their natural abundance, and its structure has been derived. This work demonstrates the pivotal role that the intramolecular hydrogen-bonding network plays in the conformational behavior of free monosaccharides.

Protein conformational diversity modulates sequence divergence

Abstract: It is well established that the conservation of protein structure during evolution constrains sequence divergence. The conservation of certain physicochemical environments to preserve protein folds and then the biological function originates a site-specific structurally constrained substitution pattern. However, protein native structure is not unique. It is known that the native state is better described by an ensemble of conformers in a dynamic equilibrium. In this work, we studied the influence of conformational diversity in sequence divergence and protein evolution. For this purpose, we derived a set of 900 proteins with different degrees of conformational diversity from the PCDB database, a conformer database. With the aid of a structurally constrained protein evolutionary model, we explored the influence of the different conformations on sequence divergence. We found that the presence of conformational diversity strongly modulates the substitution pattern. Although the conformers share several of the structurally constrained sites, 30% of them are conformer specific. Also, we found that in 76% of the proteins studied, a single conformer outperforms the others in the prediction of sequence divergence. It is interesting to note that this conformer is usually the one that binds ligands participating in the biological function of the protein. The existence of a conformer-specific site-substitution pattern indicates that conformational diversity could play a central role in modulating protein evolution. Furthermore, our findings suggest that new evolutionary models and bioinformatics tools should be developed taking into account this substitution bias.

Protein conformational diversity correlates with evolutionary rate

Abstract: Native state of proteins is better represented by an ensemble of conformers in equilibrium than by only one structure. The extension of structural differences between conformers characterizes the conformational diversity of the protein. In this study, we found a negative correlation between conformational diversity and protein evolutionary rate. Conformational diversity was expressed as the maximum root mean square deviation (RMSD) between the available conformers in Conformational Diversity of Native State database. Evolutionary rate estimations were calculated using 16 different species compared with human sharing at least 700 orthologous proteins with known conformational diversity extension. The negative correlation found is independent of the protein expression level and comparable in magnitude and sign with the correlation between gene expression level and evolutionary rate. Our findings suggest that the structural constraints underlying protein dynamism, essential for protein function, could modulate protein divergence.

Disorder and order in unfolded and disordered peptides and proteins: a view derived from tripeptide conformational analysis. II. Tripeptides with short side chains populating asx and β-type like turn conformations.

Abstract: In the preceding paper, we found that ensembles of tripeptides with long or bulky chains can include up to 20% of various turns. Here, we determine the structural and thermodynamic characteristics of GxG peptides with short polar and/or ionizable central residues (D, N, C), whose conformational distributions exhibit higher than average percentage (>20%) of turn conformations. To probe the side-chain conformations of these peptides, we determined the (3)J(H(α),H(β)) coupling constants and derived the population of three rotamers with χ1 -angles of -60°, 180° and 60°, which were correlated with residue propensities by DFT-calculations. For protonated GDG, the rotamer distribution provides additional evidence for asx-turns. A comparison of vibrational spectra and NMR coupling constants of protonated GDG, ionized GDG, and the protonated aspartic acid dipeptide revealed that side chain protonation increases the pPII content at the expense of turn populations. The charged terminal groups, however, have negligible influence on the conformational properties of the central residue. Like protonated GDG, cationic GCG samples asx-turns to a significant extent. The temperature dependence of the UVCD spectra and (3)J(H(N)H(α)) constants suggest that the turn populations of GDG and GNG are practically temperature-independent, indicating enthalpic and entropic stabilization. The temperature-independent J-coupling and UVCD spectra of GNG require a three-state model. Our results indicate that short side chains with hydrogen bonding capability in GxG segments of proteins may serve as hinge regions for establishing compact structures of unfolded proteins and peptides.

The alanine model dipeptide Ac-Ala-NH2 exists as a mixture of Ceq7 and C5 conformers

Abstract: Microwave spectroscopy has been applied to characterize the conformations adopted in the gas phase by a small peptide derived from alanine, N-acetyl-L-alaninamide (Ac-Ala-NH2). This compound was vaporized by laser ablation and shown to exist as a mixture of Ceq7 and C5 conformers stabilized by a CO⋯HN intramolecular hydrogen bond closing a seven- or a five-membered ring, respectively. The complicated quadrupole hyperfine structure originated from two 14N nuclei has been completely resolved for both species and the derived nuclear quadrupole coupling constants have been used to determine the Ramachandran angles that describe their molecular shapes.