Conformational Equilibrium In Solution Research Articles

4,4,6,6-tetrachloro-2,2-(2,2-dimethylpropane-1,3-diyldioxy)-1,3,5,2lambda5,4lambda5,6lambda5-triazatriphosphorine.

The title spirocyclic compound (alternative name: 2,2,4,4-tetrachloro-9,9-dimethyl-7,11-dioxa-1,3,5-triaza-2lambda5,4lambda5,6lambda5-triphosphaspiro[5.5]undeca-1,3,5-triene), C5H10Cl4N3O2P3, does not contain alternating long-short P-N bond lengths in the phosphazene ring [P-N 1.559 (2)-1.596 (2) A], as are observed in other analogous spirocyclic compounds. The six-membered phosphazene ring has a chair conformation in the solid state, but a conformational equilibrium in solution is indicated by NMR spectroscopy.

Determination of conformational equilibrium of peptides in solution by NMR spectroscopy and theoretical conformational analysis: application to the calibration of mean-field solvation models.

Peptides occur in solution as ensembles of conformations rather than in a fixed conformation. The existing energy functions are usually inadequate to predict the conformational equilibrium in solution, because of failure to account properly for solvation, if the solvent is not considered explicitly (which is usually prohibitively expensive). NMR data are therefore widely incorporated into theoretical conformational analysis. Because of conformational flexibility, restrained molecular dynamics (with restraints derived from NMR data), which is usually applied to determine protein conformation is of limited use in the case of peptides. Instead, (a) the restraints are averaged within predefined time windows during molecular dynamics (MD) simulations (time averaging), (b) multiple-copy MD simulations are carried out and the restraints are averaged over the copies (ensemble averaging), or (c) a representative ensemble of sterically feasible conformations is generated and the weights of the conformations are then fitted so that the computed average observables match the experimental data (weight fitting). All these approaches are briefly discussed in this article. If an adequate force field is used, conformations with large statistical weights obtained from the weight-fitting procedure should also have low energies, which can be implemented in force field calibration. Such a procedure is particularly attractive regarding the parameterization of the solvation energy in nonaqueous solvents, e.g., dimethyl sulfoxide, for which thermodynamic solvation data are scarce. A method for calibration of solvation parameters in dimethyl sulfoxide, which is based on this principle was recently proposed by C. Baysal and H. Meirovitch (Journal of the American Chemical Society, 1998, Vol. 120, pp. 800--812), in which the energy gap between the conformations compatible with NMR data and the alternative conformations is maximized. In this work we propose an alternative method based on the principle that the best-fitting statistical weights of conformations should match the Boltzmann weights computed with the force field applied. Preliminary results obtained using three test peptides of varying conformational mobility: H-Ser(1)-Pro(2)-Lys(3)-Leu(4)-OH, Ac-Tyr(1)-D-Phe(2)-Ser(3)-Pro(4)-Lys(5)-Leu(6)-NH(2), and cyclo(Tyr(1)-D-Phe(2)-Ser(3)-Pro(4)-Lys(5)-Leu(6)) are presented.

ChemInform Abstract: Structure, Conformation and Absolute Configuration of New Antifeedant Dolabellanes from Trichilia trifolia.

Abstract The structures of three new dolabellane diterpenoids, (1R,3E,7Z,11S,12S)-dolabella-3,7,18-trien-17-oic acid (1), (1R,3E,6R,7Z,11S,12S)-dolabella-3,7,18-trien-6,17-olide (2) and (1R,3S,4R,7Z,11S,12S)-3-hydroxydolabella-7,18-dien-4,17-olide (3), isolated from the wood of Trichilia trifolia, were elucidated by 1D and 2D NMR spectroscopy. The stereochemistry of 1 and 2 was confirmed by X-ray diffraction analysis, while that of 3 was ascertained from NOESY data. Comparison between experimental and calculated 1H–1H vicinal coupling constants and the analysis of molecular mechanics structures revealed that the 11-membered ring of 1 and 2 exists in a conformational equilibrium in solution, while in 3 this ring possesses a more rigid structure. The absolute configuration of 3 was established from its Cotton effects. Dolabellanes 1–3 caused significant feeding reduction by the rice weevil Sitophilus oryzae.

Structure, Conformation and Absolute Configuration of New Antifeedant Dolabellanes from Trichilia trifolia

The structures of three new dolabellane diterpenoids, (1 R,3 E,7 Z,11 S,12 S)-dolabella-3,7,18-trien-17-oic acid ( 1), (1 R,3 E,6 R,7 Z,11 S,12 S)-dolabella-3,7,18-trien-6,17-olide ( 2) and (1 R,3 S,4 R,7 Z,11 S,12 S)-3-hydroxydolabella-7,18-dien-4,17-olide ( 3), isolated from the wood of Trichilia trifolia, were elucidated by 1D and 2D NMR spectroscopy. The stereochemistry of 1 and 2 was confirmed by X-ray diffraction analysis, while that of 3 was ascertained from NOESY data. Comparison between experimental and calculated 1H– 1H vicinal coupling constants and the analysis of molecular mechanics structures revealed that the 11-membered ring of 1 and 2 exists in a conformational equilibrium in solution, while in 3 this ring possesses a more rigid structure. The absolute configuration of 3 was established from its Cotton effects. Dolabellanes 1– 3 caused significant feeding reduction by the rice weevil Sitophilus oryzae.

Synthesis and structure of (+)-2-thionosparteine, a new thioanalogue of lupanine

(+)-2-Thionosparteine was obtained for the first time. 1H and 13C NMR spectroscopy were used for quantitative determination of conformational equilibrium in solution. The X-ray structure revealed two molecules in the asymmetric unit that differ substantially in their conformations. Weak CH⋯S interactions are characterized and compared with the intramolecular hydrogen bond CH⋯O in the crystal structure of 2-oxosparteine.

Solution conformation of methylated macrolide antibiotics roxithromycin and erythromycin using NMR and molecular modelling. Ribosome-bound conformation determined by TRNOE and formation of cytochrome P450-metabolite complex

Conformational study of methylated derivatives of macrolide antibiotics roxithromycin (6-OMe-roxithromycin and 6,11-OMe-roxithromycin) has been achieved by NMR in solution and molecular dynamics (MD) simulations and compared to 6-OMe-erythromycin (clarithromycin). A complete conformational study by NMR has been led by determination of homonuclear coupling constants and NOEs. Heteronuclear 1H- 13C coupling constants were also measured to investigate the orientation of the sugar moieties with respect to the erythronolide. MD simulations were performed using the crystallographic coordinates as the starting conformation. For each compound, experimental results were compared to calculated conformations in order to identify eventual conformational equilibrium in solution. It is shown that the effect of the methylation is opposite for roxithromycin compared to erythromycin especially on motional properties as the roxithromycin derivatives gain in mobility while the erythromycin derivatives behaves as a more restrained molecule. The study of macrolide-ribosome interactions has been investigated using transferred NOESY 1H NMR experiments and the conformations weakly bound to bacterial ribosomes were determined. Biological interactions of these compounds with membranar liver protein cytochrome P450 was also discussed with regard to their structural properties.

Combined NMR and molecular modeling study of an iduronic acid-containing trisaccharide related to antithrombotic heparin fragments

An iduronic acid-containing trisaccharide, methyl-O-(4-O-methyl-2,3,6-tri-O-sulfo-α- d-glucopyranosyl-(1→4)-O-(2-O-sulfo-α- l-idopyranosyluronic acid)-(1→4)-O-2, 6-di-O-sulfo-α- d-glucopyranoside, related to antithrombotic heparin fragments has been subjected to a combined NMR and molecular modeling investigation. The conformational behavior of the two constituting disaccharide segments was investigated using a systematic grid search approach with the MM3 force field along with the proper parameters for the sulfate ester group. The exploration of the potential energy surfaces of the trisaccharide was performed through the use of the CICADA methods interfaced with the MM3 force field. In all cases, the 2-O-sulfo-α- l-iduronate moiety was given the three favored ring conformations 1C 4, 4C 1, and 2S 0 . Conformations were clustered into families, four of which are likely to exhibit significant occupancy in solution. The different low-energy conformational families display different orientations at the glycosidic linkages and/or different ring shapes for the iduronate ring. The 2 S 0 conformation is the major one for the 2-O-sulfo-α- l-iduronate but is still in equilibrium with the 1 C 4 ring shape. The occurrence of such a conformational equilibrium in solution was probed via high-resolution NMR spectroscopy through measurements of coupling constants and NOE build-up. These results are in keeping with the observation that 2- O-sulfated pentasaccharides display a similar affinity for antithrombin III as their 2- N-sulfated counterparts.

Conformational Properties of Nickel(II) Octaethylporphyrin in Solution. 1. Resonance Excitation Profiles and Temperature Dependence of Structure-Sensitive Raman Lines

We have measured polarized resonance Raman spectra of nickel(II) octaethylporphyrin in CS2 and CH2Cl2 solution at different excitation wavelengths (430−580 nm) and temperatures (190−310 K). The analysis of the spectra revealed that the structure-sensitive Raman lines ν19 and ν10 can be decomposed consistently into two sublines for all excitation wavelengths and temperatures. In the resonance region of the QO and QV bands, the 0−1 and 0−0 resonances in the excitation profiles of the low-frequency (LF) sublines of ν19 and ν10 are red-shifted by (150 (30) cm-1 with respect to the sublines that are at higher frequencies (HF). In accordance with experimental and theoretical results, this indicates that the LF sublines of ν19 and ν10 result from a nonplanar conformer, whereas the HF sublines correspond to an almost planar conformer. The existence of this known conformational equilibrium in solution is further corroborated by the van't Hoff behavior of the intensity ratios ILF/IHF of the sublines of ν19 and ν10....

Conformational equilibria of methyl α-L-arabinopyranosides in solution

Experimental NMR studies on methyl α-L-arabinopyranosides in CDCl3, pyridine and dioxane have shown that the equilibria between conformers are displaced in favour of the 4C1 conformer, except in the case of 2-substituted derivatives in CDCl3. The experimental data and a theoretical analysis aimed at explaining them in terms of intramolecular and stereoelectronic solvent effects are presented. It appears that certain electrostatic interactions and the anomeric effect, which favour 1C4 in conformational equilibria are particularly important in 2-substituted derivatives provided no disruption of intramolecular H-bridges takes place. This explains the experimental findings and throws further light on the interplay of effects which determine conformational equilibria in solution.

An application of the Miertus‐Scrocco‐Tomasi solvation model in molecular mechanics and dynamics simulations

AbstractThe point‐chart approximation of the Miertus‐Scrocco‐Tomasi solvation model (MST‐PC) based on a continuum representation of the solvent has been incorporated in force field calculations. Application in molecular mechanics (MM) involves conformational equilibria in solution: rotational isomers of ethylene glycol (I), 1,2‐difluoreothane (II), fluoroacetic acid (III), and representative conformers of macrocyclic receptors such as 18‐crown‐6 (IV), cryptand 2.2.2 (V), and t‐butyl‐calix[4]arenetetraamide (VI). Assessment of the MST‐PC results is based on the comparison with ab initio reactive field calculations (for I–III), with the continuum model of Still (W. C. Still et al., J. Am. Chem. Soc., 1990, 112, 6127) (for I–VI), and with average solute–solvent interaction energies obtained from molecular dynamics (MD) simulations with explicit solvent in water (I–VI) and in acetonitrile (IV–VI). It is demonstrated that the continuum solvent model qualitatively reproduces the trends in solvation energies in water. The few exceptions may be related to particular topological features of the solute. An improved discrete/continuum approach in which some first‐shell solvent molecules are considered as a part of the solute embedded in the dielectric continuum provides more realistic results, as is shown for VI in water. The MST‐PC model which mimics the solute–solvent electrostatic interaction only fails to reproduce conformationally dependent solvation energies in acetonitrile, in which the electrostatic contribution is relatively small compared to van der Waals interactions. Exploratory MD simulations within the continuum model in water are reported on urea and 18‐crown‐6. © 1995 by John Wiley & Sons, Inc.

Comparison of the molecular mechanics + generalized Born/surface area and the ab initio + Monte Carlo simulation methods in estimating conformational equilibria in aqueous solution

AbstractA method using molecular mechanics to calculate internal energies and the generalized Born/surface area (GB/SA) method for calculating solvation free energy has been compared with the corresponding terms obtained from ab initio quantum chemical calculations in the gas phase and the free energy perturbation method implemented in Monte Carlo (MC) simulations to study conformational equilibria in solution. 1,2‐Ethanediol, 2‐hydroxybenzoic acid, the neutral and protonated histamine, were considered in aqueous solution as systems capable of intramolecular hydrogen bonding. The molecular mechanics method with all atom and united atom models, using the AMBER* force field and the parameterization as implemented in the MacroModel modeling package and the GB/SA continuum solvation model, produces smaller separation in relative conformer free energies than does the ab initio + MC method in aqueous solution. The GB/SA relative solvation free energies using the charges from the AMBER* force fields were consistently smaller than the values obtained in Monte Carlo simulations. Using the charge sets from the Monte Carlo simulations and considering solute geometries with torsional angles fixed at the optimized ab initio values, the relative solvation free energies remained underestimated by up to 30% as compared to the Monte Carlo values. The AMBER*//GB/SA predicted most stable conformer for the 1,2‐ethandiol system in aqueous solution is in contrast with the ab initio + MC finding and the available experimental results. For the histamine system predictions by only the united atom AMBER*//GB/SA model agree with those by ab initio + MC and with data derived from nuclear magnetic resonance (NMR) experiments. Differences in the two methods are considered mainly due to the application of torsional parameters and atomic charges developed in the AMBER* parameter set for monofunctional polar systems. New parameters seem to be needed for quantitative description of the in‐solution conformational equilibria for organic compounds with a possible intramolecular hydrogen bond. © 1994 by John Wiley & Sons, Inc.

Ein neuer effizienter weg zur darstellung von glycopyranosylcyaniden (2,6-anhydroaldononitrilen) ohne nachbargruppenbeteiligung. Reduktion von 2,6-anhydro-1-desoxy-1-nitroalditolen mit phosphortrichlorid

d-Glucose, d-mannose, and d-galactose gave in two steps the corresponding per- O-acetyl-2,6-anhydro-1-deoxy-1-nitroheptitols. Treatment with phosphorus trichloride in pyridine gave directly the corresponding 3,4,5,7-tetra- O-acetyl-2,6-anhydroheptononitriles (“glycopyranosyl cyanides”). The same treatment was applied to the 3,4,5-tri- O-acetyl-2,6-anhydro-1-deoxy-1-nitrohexitols, prepared from d-xylose, d-lyxose, l-arabinose, and d-ribose, and led to the corresponding 3,4,5-tri- O-acetyl-2,6,-anhydrohexononitriles in yields ranging from 65 to 80%. No anomerization was observed, thus allowing the preparation, in high yields, of cynanides having even the 1,2- cis configuration. The anhydronitriles were compared with other known examples of this class of compounds and conformational equilibria in solution determined by 1H-n.m.r. spectroscopy. A significant anomeric effect of the cyano group is doubtful. Instead, a stabilizing effect by the 1,3-diaxial arrangement of a cyano group and an acetoxy substituent seems to be present.

ChemInform Abstract: IR Spectral Investigation of Steric Effects on the Hydrogen Bond Formation in Esters of 3‐Benzoylaminopropionic Acids. Part 4. Analysis of Conformational Equilibria in Solutions.

ChemInform Abstract: IR Spectral Investigation of Steric Effects on the Hydrogen Bond Formation in Esters of 3‐Benzoylaminopropionic Acids. Part 4. Analysis of Conformational Equilibria in Solutions.

13C n.m.r. study of conformational equilibria in solutions of methyl N‐benzoyl‐l‐leucyl‐l‐histidinate monohydrate

13C n.m.r. spectra for the title compound are reported in CDCl3 and also in pure and acidified DMSO solutions. In all cases, cis/trans isomerization about the amide bond occurs. For the cis isomers, severe steric compression shifts the ortho phenyl and leucyl β‐CH2 resonances to higher field. In CDCl3 solution, two imidazole conformations are present. In one, the imidazole group is freely rotating about the β‐CH2‐C(ring) bond, whilst the nitrogen‐bound proton participates in a dynamic tautomeric equilibrium, rapid on the n.m.r. time‐scale, between the two ring nitrogen atoms. In the other, the imidazole ring is protonated at N1 and held in a relatively rigid conformation by hydrogen‐bonding between N3, the water molecule, and the amide carbonyl group oxygen atom. The major imidazole species present in DMSO solution is the N1‐protonated tautomer. Small amounts of the N3 tautomer are also present, but in this solvent proton exchange between the two sites is slow on the n.m.r. time‐scale. In acidified DMSO, both nitrogen atoms are protonated.

Infrared-spectral investigation of steric effects on the hydrogen bond formation in esters of 3-benzoylaminopropionic acids: Part IV. An Analysis of Conformational Equilibria in Solutions

The influence of the solvent on the [NH b] ⇌ [NH f] conformational equilibrium for the t-butyl esters of 3,3-diphenyl-3- benzoylaminopropionic acid and its 2-methyl and 2,2-dimethyl-substituted analogues was investigated. The calculated Δ G B.F S values of the free-energy difference of the corresponding conformers were correlated with ϕ(ϵ S) = (ϵ S−1)/ (2ϵ S + 1) parameters, which characterize the polarity of the medium. The present results confirm our previous conclusion about the increased conformational preference in the case of the esters of 2,3-substituted 3-benzoylaminopropionic acids due to the steric interaction between the α- and β-substituents. This effect stabilizes the NH⋯O=C (ester) intramolecular hydrogen bonding which is typical of these compounds. The method of Klaeboe for IR spectral determination of conformational equilibria in solution is extended to provide better statistical confidence in the results.

Sampling methods for Monte Carlo simulations of n-butane in dilute solution

Sampling procedures for enhancing the convergence of Monte Carlo simulations of dilute solutions have been analyzed and applied to modeling n-butane in a Lennard-Jones liquid at 25 °C. The efficiency of the procedures is compared for determining structural and thermodynamic properties of the solution including the trans–gauche equilibrium for the solute. Preferential sampling of the solute plus umbrella sampling with ’’chopped’’ rotational barriers is found to be a viable means for studying conformational equilibria in solution.

Xylose Conformations of 9-β-ᴅ-Xylofuranosyladenine Analogues Modified at the 2'3' or 5'-Positions and Lyxose Conformations of 9-β-ᴅ-Lyxofuranosyladenine

Proton magnetic resonance studies of 9-β-ᴅ-xylofuranosyladenine (xyloA), its 2′-amino-2′- deoxy, 2′-azido-2′-deoxy, 2′-bromo-2′-deoxy, 3′-thio-3′-deoxy, 3′-amino-3′-deoxy, 3′-azido-3′- deoxy, 3′-chloro-3′-deoxy, 3′-fluoro-3′-deoxy, 3′-O-methyl, 3′,5′-diazido-3′,5′-dideoxy analogues and 9-β-ᴅ-lyxofuranosyladenine (lyxoA) have been carried out to study the effect of chemical modifications at the sugar moiety on the solution conformational equilibria in these classes of nucleosides. Analogously to previous studies the xylose pucker can be described in the two-state N ⇔ S model of Altona and Sundaralingam. For the xylosides, however, a somewhat different N state (C3′-endo-C4′-exo) has to be used than for the ribosides and arabinosides (C2′-exo-C3′- endo). The results of the conformational analysis are that xyloA exists almost exclusively as an N conformed The effect of the substitutions in the modified compounds is to destabilize the N state. This decrease in the mole fraction of N is accompanied by an increase in the population of the g+ rotamer of the exocylic 5′-CH2OD group. Thus for the xylosides a correlation N-t/g- or S- g+, respectively, can be derived. Proton relaxation rate measurements on 2′-azido-2′-deoxyxylo- furanosyladenine indicate that in the xylosides the standard syn or anti ranges do not represent stable positions for the adenine base, but that a glycosyl torsion angle (Χ∼160°, Υ∼80°) be­ tween syn and anti is preferred. LyxoA behaves similar to the xylosides and also favours the N state of the sugar pucker. In a summarizing discussion the conformational equilibria of the different modified pentosides - ribose, arabinose, xylose and lyxose - are compared. It is shown that generally intramolecular hydrogen bonding does not yield an important contribution to the stabilization of conformational equilibria in solution. It is also not possible to derive a quantitative relationship between such parameters as Van-der-Waals’ radii or electronegativity of the substituents and the mole fractions of the different conformers. It can, however, be seen that in all cases, where the hydroxyl groups at C2′ or C3′ are substituted by a more voluminous atom or group, steric effects become dominant and allow a qualitative explanation of the changes of the conformational equilibria. Only for the smallest and most electronegative substituents, like fluorine, other interactions (e.g. electrostatic) may become important. It is thus suggested that the purine(β)nucleoside conforma­tion is essentially determined by steric interactions between the different parts of the molecule.

Change of the molecular surface and volume during internal rotation and its effect on conformational equilibrium in solution

Conformational dependence of the molecular surface S and molecular volume V for hexane and 1,1,2-trichloroethane during rotation around a central bond in the molecules have been calculated. A model of overlapping spheres is used, the size of the spheres being determined by Van der Waals radii of individual atoms. Plots of S and V against torsional angle φ are compared with the potential of internal rotation of both molecules E(φ). The calculated molecular surfaces and volumes of the two molecules for the most stable conformers mutually differ by several percent as experimental results also indicate. We also show that the differences in S and V between individual conformers always affect conformational equilibrium in solution even if solvent-solute interaction energies are not explicitly considered. As a consequence of the mentioned volume changes during internal rotation in a molecule, the conformational energies for hydrocarbons in the condensed and gaseous phases can differ by as much as several kJ mol −1.

ChemInform Abstract: UPDATING THE MOLECULAR‐MECHANICAL FORCE FIELD FOR ORGANIC HALIDES

In extension of previous molecular mechanical studies of organic halides, we examine three pathways to enlarge the scope of the force field. These are: adaptation of the constants to a new formulation of the basic force field; substitution of the monopole for the dipole approximation, in evaluating the electrostatic strain; estimation of solvation energies and conformational equilibria in solution. The structures studied are mono- and non-geminal dihaloalkanes, and monohaloketones (fluorides, chlorides, bromides). We discuss the quantitative separation of steric and electrostatic effects in halocyclohexanones, and identity the minimum-energy rotamers in haloacetones.

Updating the Molecular–Mechanical Force Field for Organic Halides

AbstractIn extension of previous molecular mechanical studies of organic halides, we examine three pathways to enlarge the scope of the force field. These are: adaptation of the constants to a new formulation of the basic force field; substitution of the monopole for the dipole approximation, in evaluating the electrostatic strain; estimation of solvation energies and conformational equilibria in solution. The structures studied are mono‐ and non‐geminal dihaloalkanes, and monohaloketones (fluorides, chlorides, bromides). We discuss the quantitative separation of steric and electrostatic effects in halocyclohexanones, and identity the minimum‐energy rotamers in haloacetones.