β‐Turn Analogues in Model αβ‐Hybrid Peptides: Structural Characterization of Peptides Containing β2,2Ac6c and β3,3Ac6c Residues

The effect of gem‐dialkyl substituents on the backbone conformations of β‐amino acid residues in peptides has been investigated by using four model peptides: Boc‐Xxx‐β^2,2Ac₆c(1‐aminomethylcyclohexanecarboxylic acid)‐NHMe (Xxx=Leu ( 1 ), Phe ( 2 ); Boc=tert‐butyloxycarbonyl) and Boc‐Xxx‐β^3,3Ac₆c(1‐aminocyclohexaneacetic acid)‐NHMe (Xxx=Leu ( 3 ), Phe ( 4 )). Tetrasubstituted carbon atoms restrict the ranges of stereochemically allowed conformations about flanking single bonds. The crystal structure of Boc‐Leu‐β^2,2Ac₆c‐NHMe ( 1 ) established a C₁₁ hydrogen‐bonded turn in the αβ‐hybrid sequence. The observed torsion angles (α(?≈?60°, ψ≈?30°), β(?≈?90°, θ≈60°, ψ≈?90°)) corresponded to a C₁₁ helical turn, which was a backbone‐expanded analogue of the type III β turn in αα sequences. The crystal structure of the peptide Boc‐Phe‐β^3,3Ac₆c‐NHMe ( 4 ) established a C₁₁ hydrogen‐bonded turn with distinctly different backbone torsion angles (α(?≈?60°, ψ≈120°), β(?≈60°, θ≈60°, ψ≈?60°)), which corresponded to a backbone‐expanded analogue of the type II β turn observed in αα sequences. In peptide 4 , the two molecules in the asymmetric unit adopted backbone torsion angles of opposite signs. In one of the molecules, the Phe residue adopted an unfavorable backbone conformation, with the energetic penalty being offset by a favorable aromatic interaction between proximal molecules in the crystal. NMR spectroscopy studies provided evidence for the maintenance of folded structures in solution in these αβ‐hybrid sequences.     

Proton NMR study on two structures of 3′-O-(acetylimino)3′-de(phosphinico)-thymidylyl-(3,5′)-deoxythymidine in aqueous solution

The solution structure of one of dithymidine monophosphate (TpT) analogues, containing an (N-acetyl)imino backbone linkage (NCOCH₃) of 3′-O-(acetylimino)3′-de(phosphinico)-thymidylyl-(3,5′)-deoxythymidine (T_NT), has been determined by proton NMR. Two structures, designated as major and minor forms, in a ratio of about 3:2 coexist when the solution temperature is <25°C. Both forms adopt anti conformation with respect to the glycosidic bond, S-type deoxyribofuranose pucker, and have no base stacking. The backbone torsion angles ε′, φ_ON, φ_NC, and γ′ are trans, gauche⁺, gauche⁺, and gauche⁺ for the major form; and gauche⁻, gauche⁻, gauche⁻, and gauche⁺ for the minor form. Only major form is found at >25°C.     

The Influence of the Amino Acid Side Chains on the Raman Optical Activity Spectra of Proteins

The Raman optical activity (ROA) spectra of proteins show distinct patterns arising from the secondary structure. It is generally believed that the spectral contributions of the side-chains largely cancel out because of their flexibility and the occurrence of many side-chains with different conformations. Yet, the influence of the side-chains on the ROA patterns assigned to different secondary structures is unknown. Here, the first systematic study of the influence of all amino acid side-chains on the ROA patterns is presented based on density functional theory (DFT) calculations of an extensive collection of peptide models that include many different side-chain and secondary structure conformations. It was shown that the contributions of the side-chains to a large extent average out with conformational flexibility. However, specific side-chain conformations can have significant contributions to the ROA patterns. It was also shown that α-helical structure is very sensitive to both the exact backbone conformation and the side-chain conformation. Side-chains with χ₁≈−60° generate ROA patterns alike those in experiment. Aromatic side-chains strongly influence the amide III ROA patterns. Because of the huge structural sensitivity of ROA, the spectral patterns of proteins arise from extensive conformational averaging of both the backbone and the side-chains. The averaging results in the fine spectral details and relative intensity differences observed in experimental spectra.     

n-Propyl cyanide and isocyantde: rotational and structural isomerization

Ab initio calculations with an STO-3G basis and geometry optimization have been performed on n-propyl cyanide and isocyanide in four rotational conformations, trans, cis, and gauche, with, in the latter case, two different dihedral angles, 90° and 120° from the trans position, being employed. The trans and gauche 120° isomers are predicted to be the most stable for both the cyanide and isocyanide, and the cyanide—isocyanide energy difference is calculated to be approximately 22 kcal mole^?1 for each rotational isomer. The results of a population analysis are employed to discuss the electronic structures of the cyanide, isocyanide, and the isomerization process.     

Spectra and structure of small ring compounds: Part XXXVIII. Cyclobutanol

The Raman spectrum of gaseous cyclobutanol has been recorded and the far infrared spectrum of the gas has been obtained at a resolution of 0.5 cm^?1. At least six Q-branches arising from the low frequency ring-puckering motion have been observed and assigned on the basis of a potential of the form V(X) = (6.32 ± 0.21) × 10⁵X⁴?(4.18 ± 0.04) × 10⁴X²+ (8.81 ± 1.20) × 10³X³ with a reduced mass of 170 amu. An energy difference between the equatorial and axial forms was found to be 50–150 cm^?1 with the equatorial being more stable and a barrier of 700–900 cm^?1 was found for the interconversion. Three O-H stretching modes were observed in the Raman spectrum. It is concluded that the O-H moiety has both the gauche and trans conformations present in the equatorial form but only the gauche conformer is present in the axial form of the ring. Three O-H torsional modes were observed at 244 (trans conformer), 226.5 and 181.5 cm^?1 (gauche conformer) for the equatorial form and one O-H torsion at 237.5 cm^?1 (gauche conformer) for the axial form. The potential function governing the O-H torsional motion for the equatorial form was found to be V₁ = 280 ± 7 cm^?1 (800 cal mole^?1) and V₃ = 425 ± 3 cm^? (121.5 cal mole^?1) with the trans conformer being more stable than the gauche by approximately 206 cm^?1 (589 cal mole^?). The barriers to trans-gauche and gauche-gauche interconversion have essentially the same values, 500 cm^?1 (1430 cal mole^?1).     

A conformational study of aromatic imide compounds. Part 2. Compounds containing diphenyl sulfide,diphenyl sulfone,and diphenylmethane moieties

An attempt was made to estimate the dihedral angles, φ, ψ, ω₁, and ω₂, of bis(4-hydroxyphthalimide)s (BHPI) and bis(phenylphthalimide)s (BPI) having diphenyl sulfide, diphenyl sulfone, or diphenylmethane linkages at the center of molecules using solid–state ¹³C CP/MAS NMR and ab initio nuclear shielding calculations. The TOSS and TOSS & DD pulse sequences were performed in the NMR measurements to obtain exact chemical shifts of each carbon. Total energies were calculated using the B3LYP/6-31G(d) level of theory, and shielding constants were calculated using the RHF/6-31G(d) level of theory for diphenyl sulfide, diphenyl sulfone, diphenylmethane with varying angles of φ, ψ from 0 to 180° at intervals of 10°. It was clarified that the –S– and –SO₂– linkages lead asymmetrical conformations with different ω₁ and ω₂ or with different φ and ψ for BHPIs and BPIs. In contrast, the compounds having –CH₂– linkages have symmetrical conformations. The dihedral angle of imide ring and phenylene ring (ω) are in the range of 40–90°, and the dihedral angles (φ,ψ) distribute in the stable regions of the energy surfaces ranging from 40 to 90°.     

Closing the side-chain gap in protein loop modeling

The success of structure-based drug design relies on accurate protein modeling where one of the key issues is the modeling and refinement of loops. This study takes a critical look at modeled loops, determining the effect of re-sampling side-chains after the loop conformation has been generated. The results are evaluated in terms of backbone and side-chain conformations with respect to the native loop. While models can contain loops with high quality backbone conformations, the side-chain orientations could be poor, and therefore unsuitable for ligand docking and structure-based design. In this study, we report on the ability to model loop side-chains accurately using a variety of commercially available algorithms that include rotamer libraries, systematic torsion scans and knowledge-based methods. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

NMR studies of conformations and dynamic processes—II : [26]Bicyclophanes with ethylene bridges

The conformations and dynamic processes in two bicyclophanes have been analysed on the basis of temperature-dependent ¹H NMR spectra. Both bicyclophanes are suggested to have a lowest-energy conformation of D₃ symmetry in which the substituents at all ethylene bridges are gauche⁺ (or gauche^?) oriented. The interconversion of the mirror image conformers of each bicyclophane equilibrates the two hydrogens in each methylene group, the barriers being ca 36 and 37 kJ mol^?1, respectively, as determined by line-shape analysis.     

A new method for side-chain conformation prediction using a Hopfield network and reproduced rotamers

We present a new side-chain prediction method based on energy minimization using a Hopfield network, focusing on the buried residues of proteins. In this method, the network is composed of automata assigned to each rotamer to restrict side-chain conformational space. We reproduced a rotamer library that enabled us to more widely cover the space for side-chain conformations than those previously produced. The accuracy of the side-chain modeling was estimated by three standards: root mean square deviations (rmsds) between the modeled and the crystal structures, the percentages of correctly predicted side-chain torsion angles, and the percentages of correctly predicted hydrogen bonds. The average rmsd for buried side chains of 21 proteins was 1.10 Å. The value was almost always improved relative to the previous works. The percentage of side-chain X₁ angles for buried residues was 87.3%. By considering the hydrogen bond energy, the average percentage of correctly predicted hydrogen bonds rose from 33% without hydrogen bond energy to 52% with the bond energy. We applied this method to homology modeling, where the protein backbone used to predict side-chain conformations deviates from the correct conformation, and could predict side-chain conformations as correctly as those using the correct backbones. © 1996 by John Wiley & Sons, Inc.     

Redetermination of sperminium tetrachloride

In the title compound, 1,5,10,14‐tetraazoniatetra­decane tetrachloride, C₁₀H₃₀N₄⁴⁺·4Cl⁻, the sperminium tetracation lies on a centre of symmetry. The two central C—N—C—C torsion angles are gauche and of opposite signs, and all the other torsion angles are trans. All NH groups participate in the three‐dimensional hydrogen‐bond network, which is additionally strengthened by C—H⋯Cl interactions.     

Peptide models XVI. The identification of selected HCO—L—SER—NH2 conformers via a systematic grid search using ab initio potential energy surfaces

Multidimensional conformational analysis (MDCA) predicted the existence of nine stable backbone conformations (α_L, α_D, β_L, γ_L, γ_D, δ_L, δ_D, ϵ_L, and ϵ_D) on the 2D-Ramachandran map, E = E(ϕ, ψ), for a single amino acid diamide (HCONH-CHR-CONH₂). The potential energy hypersurfaces (E = E[ϕ, ψ, χ₁, χ₂]) of For-L-Ser-NH₂ associated with the α_L-, bgr;_L-, γ_L-, δ_L-, and ϵ_L-type stable backbone orientations are investigated in this article. An appropriate number of side-chain rotamers is associated with each of the backbone conformers. In the case of serine, where R = −CH₂OH, the two sidechain torsional angles (χ₁, χ₂) should lead to 3 * 3 = 9 different sidechain orientations according to MDCA. For certain backbone structures, some of the sidechain conformations were nonexistent. © 1996 by John Wiley & Sons, Inc.     

Methyl 2‐O‐β‐d‐glucopyranosyl‐α‐l‐rhamnopyranoside

The overall conformation of the title compound, C₁₃H₂₄O₁₀, is described by the glycosidic torsion angles ?_H (H1_g—C1_g—O2_r—C2_r) and ψ_H (C1_g—O2_r—C2_r—H2_r), which have values of 13.6 and 16.1°, respectively. The former is significantly different from the value predicted by consideration of the exo‐anomeric effect (?_H～ 60°) and from that in solution (?_H～ 50°), as determined previously by NMR spectroscopy. An intramolecular O3_r—H?O2_g hydrogen bond may help to stabilize the conformation in the solid state. The orientation of the hydroxy­methyl group of the glucose residue is gauche–gauche, with a torsion angle ω (O5_g—C5_g—C6_g—O6_g) of ?70.4 (4)°. Both pyranose rings are in their expected chair conformations, i.e.⁴C₁ for d ‐glucose and ¹C₄ for l ‐rhamnose.     

The gas-phase rotamers of 1,1,2,2-tetrafluoroethane - force field,vibrational amplitudes and geometry - a joint electron-diffraction and spectroscopic study

The gas-phase conformational mixture of the anti and gauche rotamers of 1,1,2,2-tetrafluoroethane has been subjected to an electron-diffraction study at 253 K. Effective least-squares refinement of the geometry and relative proportions of the conformers was achieved with vibrational amplitudes for both conformers fixed at values calculated from spectroscopic data. In order to calculate the amplitudes, a force field was deduced which reproduced the observed wave numbers for both conformers; the assignment of the modes proposed in the literature was modified slightly. At 253 K, the rotamer composition was found to be 84% anti : 16%gauche, which corresponds to an energy difference of 1170 cal mol^?1; the geometrical parameters (r_a values) and e.s.d. are C-C = 1.518 ± 0.005 Å, C-H = 1.098 ± 0.006 Å, C-F = 1.350 ± 0.002 Å. ∠CCF = 108.2 ± 0.3°, ∠FCF = 107.3 ± 0-3°, ∠ CCH = 110.3 ± 1.0δ, and the torsion angleτ _hcch in the gauche form is 78 ± 2°.     

Characterization of structural transitions from aqueous solution to a lipid phase for α-MSH

Fluorescence spectroscopy results show that the α-melanocyte-stimulating hormone peptide (α-MSH) interacts with acidic lipid vesicles. Detectable structural changes are concomitant with the passage of a tryptophan residue from aqueous to lipidic media. The observed multiexponential decay of fluorescence, rationalized as originating from three rotameric populations of the tryptophan residue, has been used together with a matrix algorithm to find the most probable conformational families of α-MSH in water and lipid environments. A model is discussed in which the same conformational families occur in various phases, although with different probabilities. A conformational family in which χ₁ of the Trp9 side chain is in the trans-rotameric conformation is shown to have structural features highly appropriate to interact with negatively charged biological membranes, which are also in accordance with previous molecular dynamics simulations and with structures engineered in α-MSH analogs that show an increased potency in biological essays. The gauche minus and gauche plus side-chain conformations of Trp9, on the other hand, yield conformations more likely to predominate in aqueous solution. NMR spectroscopy measurements of α-MSH analogs indicate the existence in aqueous solution of a β strand in the vicinity of Trp9. A similar structural feature was found in the present conformational analysis for the gauche minus and gauche plus side-chain rotamers of Trp9. © 1995 John Wiley & Sons, Inc.     

Methyl 4‐O‐benzoyl‐2,3‐O‐isopropyl­idene‐α‐l‐rhamnopyran­oside

The title compound, C₁₇H₂₂O₆, has an exocyclic ester group at the hexopyranosyl sugar residue. The carbonyl group shows a conformation that is eclipsed with respect to the adjacent ring C—H bond. The two ester torsion angles are denoted by syn and cis conformations. One of these torsion angles is indicated to have a similar conformation in solution, as analyzed by NMR spectroscopy and a Karplus‐type relationship.     

Thiocyclosporins: Preparation,Solution and Crystal Structure,and Immunosuppressive Activity

The reaction of cyclosporin A (CsA) with Lawesson's reagent under different conditions yields various thiocyclosporins, in which carbonyl O-atoms and/or the hydroxy O-atom of the MeBmt residue are replaced by an S-atom. The position of the S-atom is determined by NMR spectroscopy, and the conformations of the products are studied by NMR spectroscopy and X-ray crystallography. Some of the thiocyclosporins show interesting conformational properties. Whereas one conformation strongly dominates for CsA in CDCL₃, two conformers A and B, in a ratio 58:42 are found for [¹ψ², CS–NH]CsA. Extensive NMR studies including new 2D and 3D heteronuclear techniques and restrained MD calculations using ROE effects demonstrate that the major conformer A is identical to CsA, while the minor conformer B contains an additional cis peptide bond between the Sar³ and MeLeu⁴ residues. [⁴ψ⁵, CS? NH; ⁷ψ⁸, CS–NH]CsA exhibits a conformation very similar to crystalline CsA. However, the D-Ala⁸NH, MeLeu⁶Co γ-turn H-bond is not present in this dithio analogue. Also different is the MeBmt¹side-chain conformation, the dithio conformation showing a strong MeBmt¹OH, Sar³CO H-bond. Immunosuppressive activities of thiocyclosporins are measured in IL-2 and IL-8 reporter gene assays. Their activities are discussed in relation to their conformations.     

The role of internal H-bonding in the conformational preferences of some molecules of the formula CH3CHYCH2X

The conformational energies of 1-amino-2-propanol, 2-amino-1-propanol and 1,2-diaminopropane are studied using ab initio molecular orbital theory employing minimal (STO-3G) and extended (4-31G) basis sets. Calculations at both levels of theory generally favor conformations stabilized by internal H-bonding for all molecules considered. Results are first presented for conformations employing assumed geometries. Since the conformational energy differences as found by the initial set of calculations are in some cases rather small it then becomes necessary to introduce geometry optimizations into the study at the minimal STO-3G level. In addition, to get a better estimate of the energy differences of the various conformations 4-31G calculations are performed on the STO-3G optimized structures. These latter results indicate the following, (a) For 1-amino-2-propanol only one conformation that is stabilized by intramolecular H-bonding is low in energy; this has the methyl and amino groups anti. The other H-bonded conformer, where the methyl and amino groups are gauche, is predicted to be ca. 1.2 kcal mol^?1 less stable. Similar findings for this molecule have recently been provided by micro-wave spectroscopy. (b) For 2-amino-1-propanol the two H-bonded conformers are only separated by about 0.5 kcal mol^?1, with the anti conformer being more stable. Micro-wave spectroscopy again supports these calculations. (c) For 1,2-diaminopropane the gauche conformer is predicted to be of rather high energy (ca. 2.5 kcal mol^?1) compared to the corresponding anti H-bonded conformer. The value of 2.5 kcal mol^?1should be taken as an upper limit, since the geometry optimization of the gauche conformer of 1,2-diaminopropane is incomplete compared to the optimization carried out for the anti conformer.     

Vibrational analysis of 1-iodopropane, 1-iodobutane and 1,3-diiodopropane

Normal coordinate calculations were made for the trans and gauche conformations of n-propyl and n-butyl iodides and for the tt, tg and gg conformations of 1,3-diiodopropane. Nineteen force constants of a 48-parameter modified valence force field were adjusted to provide the best fit for 114 frequencies (excluding C-H) of all these conformations except for gg, 1,3-di-iodopropane. The average difference between observed and calculated wavenumbers was 6.6 cm^?. Previous vibrational assignments were revised.     

Rotational isomemsm in difluoroacetyl fluoride: Part II. AB initio calculations

The potential energy function for internal rotation of difluoroacetylfluoride around the C-C axis has been obtained by ab initio SCF calculations in a Gaussian basis set. Two minima are predicted with H and F atoms trans (α = O²) and gauche (α = 107–108°), respectively. Gauche- DFAF is incorrectly predicted to have the lower energy, but the addition or bond functions to the basis reduces the gauche-trans energy difference to ?0.1 kcal mole^?1. Dipole moments and torsional excitation energies are reported for both conformations and the significance of the computed potential function is critically analyzed. No support has been found for the suggestion that the C-F bonds in the CHF₂-group of gauche-DFAF are significantly different.