Solution-state Conformations Research Articles

Synthesis and conformations of phosphine- and phosphinite-derivatized resorcinarenes

The synthesis of resorcinarene derivatives with four or eight alkynyldiphenylphosphine or diphenyl phosphinite functional groups is reported. The tetraphosphinite derivatives have effective C2v symmetry and have the potential to adopt two different boat conformations in which the arene groups with phosphinite substituents are horizontal or vertical. A method for the determination of the solution-state conformation of the resorcinarene skeleton using correlated 1H and 13C NMR data is reported, and the boat conformation of one tetraphosphinite compound in the solid state has been determined crystallographically.Key words: phosphine, phosphinite, resorcinarene, conformation.

Conformation of the galactose ring adopted in solution and in crystalline form as determined by experimental and DFT 1H NMR and single-crystal X-ray analysis.

The solution-state conformations of various galactose derivatives were determined by comparison of the experimental (1)H-(1)H vicinal coupling constants to those calculated using density functional theory (DFT) at the B3LYP/cc-pVTZ//B3LYP/6-31G(d,p) level of theory. The agreement between the experimental and calculated vicinal coupling constants for 1,2:3,4-di-O-isopropylidene-alpha-d-galactopyranose was good, thereby confirming an (O)S(2) skew conformation for it and its derivatives on the basis of their similar observed couplings. Single-crystal X-ray analysis of 1,2:3,4-di-O-isopropylidene-6-O-(3,4,6-tri-O-acetyl-2-deoxy-2-N-phthalimido-beta-d-glucopyranosyl)-alpha-d-galactopyranose and 1,2,3,4,6-penta-O-acetyl-alpha-d-galactopyranose provided (O)S(2) and (4)C(1) conformations, respectively, for the galactose ring in the solid state. The solid-state structures proved to be suitable starting structures for further DFT structure refinement or for immediate calculation of the coupling constants.

Solution- and bound-state conformational study of N,N',N"-triacetyl chitotriose and other analogous potential inhibitors of hevamine: application of trNOESY and STD NMR spectroscopy.

The solution-state conformations of N,N',N"-triacetyl chitotriose (1) and other potential chitinase inhibitors 2-4 were studied using a combination of NMR spectroscopy (NOESY) and molecular mechanics calculations. Determination solely of the global energy minimum conformation was found to be insufficient for an agreement with the NMR results. An appropriate consistency between the NMR experimental data and theoretical calculations was only reached by assessing the structures as population-weighted average conformers based on Boltzmann distributions derived from the calculated relative energies. Analogies, but also particular differences, between the synthetic compounds 2-4 and the naturally-occurring N,N',N"-triacetyl chitotriose were found. Furthermore, the conformation of compounds 1 and 2 when bound to hevamine was also studied using transferred NOESY experiments and the binding process was found to impart a level of conformational restriction on the ligands. The preferred conformation as determined for 1 in the bound state to hevamine belonged to one of the conformational families found for the compound when free in solution, although full characterisation of the bound-state conformations was impeded due to severe signal overlap. Saturation transfer difference NMR experiments were also employed to analyse the binding epitopes of the bound compounds. We thus determined that it is mainly the acetyl amido groups of the trisaccharide and the heterocyclic moiety which are in close contact with hevamine.

Determination of molecular stereochemistry using vibrational circular dichroism spectroscopy: absolute configuration and solution conformation of 5-formyl-cis, cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid lactone.

The determination of the absolute configuration of chiral molecules is an important aspect of molecular stereochemistry. Vibrational circular dichroism (VCD) is the extension of electronic CD into the infrared region where fundamental vibrational transitions occur. VCD has a number of advantages over all previous methods of absolute configuration assignment. The absolute configuration and predominant solution-state conformation in CDCl(3) of the chiral lactone, 5-formyl-cis,cis-1,3,5-trimethyl-3-hydroxymethylcyclohexane-1-carboxylic acid lactone, 1, obtained by the comparison of measured and calculated VCD spectra, are reported. It is found that (-)-1 corresponds to the absolute configuration (1S,3S,5R)-1.

Axinellin C, a Proline‐Rich Cyclic Octapeptide Isolated from the Fijian Marine Sponge Stylotella aurantium.

The structure of a new cyclic octapeptide, axinellin C, (cyclo[Thr1-Val2-Pro3-Trp4-Pro5-Phe6-Pro7-Leu8]), with all-trans peptide bond geometry, was elucidated by a combination of 2D NMR methods and tandem mass spectrometry. The solution state conformation was determined by ROE restrained molecular dynamics calculations. The structural features were found to be similar to those of the crystal structure of the cyclic decapeptide, phakellistatin 8, despite differing peptide sequences.

Absolute configuration determination of chiral molecules in the solution state using vibrational circular dichroism.

Advances in the measurement, calculation, and application of vibrational circular dichroism (VCD) for the determination of absolute configuration are described. The purpose of the review is to provide an up-to-date perspective on the capability of VCD to solve problems of absolute stereochemistry for chiral molecules primarily in the solution state. The scope of the article covers the experimental methods needed for the accurate measurement of VCD spectra and the theoretical steps required to systematically deduce absolute configuration. Determination of absolute configuration of a molecule by VCD requires knowledge of its conformation or conformational distribution, and hence VCD analysis necessarily provides solution-state conformation information, in many cases available by no other method, as an additional benefit. Comparisons of the advantages and limitations of VCD relative to other available chiroptical methods of analysis are also presented.

Homonuclear Selective One-Dimensional Gradient NMR Experiments in the Structure Determination of Natural Diterpene Derivatives

The solution structure of two natural diterpene derivatives, the secondary metabolites esulatin-A and esulatin-B of Euphorbia esula, was investigated by homonuclear NMR experiments. Since the spectral dispersion of the 1H NMR spectra at 500 MHz was sufficient to separate several skeletal protons of the title compounds, they were selectively excited with a double pulsed field gradient spin-echo (DPFGSE) sequence using 180°Gaussian pulses sandwiched between sine shaped gradients. With the use of selective excitation, scalar as well as dipolar interactions of the selected spins were monitored through one-dimensional (1D) COSY, TOCSY, and NOESY experiments. The chemical shifts of the coupling partners could be accurately extracted from the 1D COSY and TOCSY spectra recorded with high digital resolution. The selective TOCSY experiment provided an excellent opportunity to identify spins belonging to the same scalarly coupled spin system. The solution state conformation was investigated by selective gradient enhanced NOESY experiments. Proton–proton distances were evaluated from the cross-relaxation rates obtained from a quantitative analysis of the NOESY spectra recorded with different mixing times. The NMR derived distances were compared to the results of solid state X-ray diffraction measurements.

Axinellin C, a proline-rich cyclic octapeptide isolated from the Fijian marine sponge Stylotella aurantium

The structure of a new cyclic octapeptide, axinellin C, (cyclo[Thr 1-Val 2-Pro 3-Trp 4-Pro 5-Phe 6-Pro 7-Leu 8]), with all- trans peptide bond geometry, was elucidated by a combination of 2D NMR methods and tandem mass spectrometry. The solution state conformation was determined by ROE restrained molecular dynamics calculations. The structural features were found to be similar to those of the crystal structure of the cyclic decapeptide, phakellistatin 8, despite differing peptide sequences.

Preparation of 1,2- O-isopropylidene derivatives of α- d-galactoseptanose, β- l-altroseptanose, and 3- O-methyl-α- d-guloseptanose

Displacement of the tosyloxy group in 5- O-benzyl-1,2- O-isopropylidene-4- O-( p-toluenesulfonyl)-α- d-glucoseptanose has yielded derivatives of 1,2- O-isopropylidene-α- d-galactoseptanose. Acid catalysed acetonation then gave 1,2:3,4-di- O-isopropylidene-α- d-galactoseptanose or 1,2;4,5-di- O-isopropylidene-α- d-galactoseptanose using lower acid concentrations. Reduction of the ketone derived from 1,2:3,4- O-isopropylidene-α- d-septanose gave 1,2;3,4-di- O-isopropylidene-β- l-altroseptanose. Reaction of 3,4-anhydro-5- O-benzyl-1,2- O-isopropylidene-α- d-galactoseptanose with sodium methoxide gave 5- O-benzyl-1,2- O-isopropylidene-4- O-methyl-α- d-glucoseptanose and 5- O-benzyl-1,2- O-isopropylidene-3- O-methyl-α- d-guloseptanose. Solution-state conformations of these compounds have been deduced from their 1H NMR spectra.

Metal binding of Lissoclinum patella metabolites. Part 2: Lissoclinamides 9 and 10

Studies on the Thz, Thn and Oxn containing cyclic peptides, lissoclinamides 9 (9) and 10 (10) isolated from the Indo-Pacific ascidian (seasquirt) Lissoclinum patella have delineated their metal binding selectivity. MS and CD competition studies show that lissoclinamide 10 (10) shows selectivity for Cu2+ in the presence of an excess of Zn2+ whereas lissoclinamide 9 (9) is less selective for Cu2+. Comparison of the solution state conformations derived from nOe restrained molecular dynamics and additional Monte–Carlo conformational searches suggested binding environments for the Cu2+ which confirmed the MS measurements and suggested a reason for the selectivity in the case of lissoclinamides 9 and 10.

Solution and solid state conformation of Fischer carbene complexes vis-à-vis conformation of aryl carboxamides: complexation of the aromatic ring by tricarbonylchromium makes a difference

Abstract Crystallography and proton NMR spectroscopy were used to compare the conformations of aryl amino Fischer carbene complexes with structurally analogous aryl carboxamides. The similarity disappears when the aromatic rings were complexed with tricarbonylchromium groups. Details of synthesis, spectral and analytical data for all new compounds are provided.

Structural characterization of adenine nucleotides bound to Escherichia coli adenylate kinase. 1. Adenosine conformations by proton two-dimensional transferred nuclear Overhauser effect spectroscopy.

Adenosine conformations of adenosine 5'-triphosphate (ATP) and adenosine 5'-monophosphate (AMP), and of an ATP analogue, adenylyl imidodiphosphate (AMPPNP), bound to Escherichia coliadenylate kinase (AKe) in the complexes of AKe.Mg(II)ATP, AKe.AMP.Mg(II)GDP, AKe. AMPPNP, and AKe.Mg(II)AMPPNP were determined by transferred two-dimensional nuclear Overhauser effect spectroscopy (TRNOESY) measurements and molecular dynamics simulations. The glycosidic torsion angles, chi, deduced for the adenine nucleotides in these complexes are 51 degrees, 37 degrees, 49 degrees, and 47 degrees, respectively, with an experimental error of about +/-5 degrees. These values are in general agreement with those previously measured for other ATP-utilizing enzymes, suggesting a possible common motif for adenosine recognition and binding. The pseudorotational phase angle, P, of the sugar puckers for the bound nucleotides varied between 50 degrees and 103 degrees. These solution-state conformations are significantly different from those in published data from X-ray crystallography. A computation of the ligand NOEs, made by using the program CORCEMA [Moseley, H. N. B., Curto, E. V., and Krishna, N. R. (1995) J. Magn. Reson. B108, 243-261] with the protein protons in the vicinity of nucleotide included, on the basis of the X-ray structure of the AKe.AMP.AMPPNP complex [Berry, M. B., Meador, B., Bilderback, T., Liang, P., Glaser, M., and Philips, G. N. , Jr. (1994) Proteins: Struct., Funct., Genet. 19, 183-198], showed that polarization transfer to the protein protons does not produce significant errors in the structures determined by considering the ligand NOEs alone.

Orienting domains in proteins using dipolar couplings measured by liquid-state NMR: differences in solution and crystal forms of maltodextrin binding protein loaded with β-cyclodextrin

Protein function is often regulated by conformational changes that occur in response to ligand binding or covalent modification such as phosphorylation. In many multidomain proteins these conformational changes involve reorientation of domains within the protein. Although X-ray crystallography can be used to determine the relative orientation of domains, the crystal-state conformation can reflect the effect of crystal packing forces and therefore may differ from the physiologically relevant form existing in solution. Here we demonstrate that the solution-state conformation of a multidomain protein can be obtained from its X-ray structure using an extensive set of dipolar couplings measured by triple-resonance multidimensional NMR spectroscopy in weakly aligning solvent. The solution-state conformation of the 370-residue maltodextrin-binding protein (MBP) loaded with β-cyclodextrin has been determined on the basis of one-bond 15N-H N, 15N- 13C′, 13C α- 13C′, two-bond 13C′-H N, and three-bond 13C α-H N dipolar couplings measured for 280, 262, 276, 262, and 276 residues, respectively. This conformation was generated by applying hinge rotations to various X-ray structures of MBP seeking to minimize the difference between the experimentally measured and calculated dipolar couplings. Consistent structures have been derived in this manner starting from four different crystal forms of MBP. The analysis has revealed substantial differences between the resulting solution-state conformation and its crystal-state counterpart (Protein Data Bank accession code 1DMB) with the solution structure characterized by an 11(±1)° domain closure. We have demonstrated that the precision achieved in these analyses is most likely limited by small uncertainties in the intradomain structure of the protein (ca 5° uncertainty in orientation of internuclear vectors within domains). In addition, potential effects of interdomain motion have been considered using a number of different models and it was found that the structures derived on the basis of dipolar couplings accurately represent the effective average conformation of the protein.

Solution and solid state conformation of the human EGF receptor transmembrane region

The epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase family of signalling cell surface molecules. Signalling by this protein is mediated through binding of epidermal growth factor to its extracellular region ultimately leading to phosphorylation of several residues on the intracellular portion of the receptor. The only means of communication between the intracellular and extracellular domains is via the transmembrane region of the protein. In this work we describe the first structural studies of a 34-residue synthetic peptide (hEGFRp), representative of the human EGFR transmembrane region, using two-dimensional and 2 H wideline NMR and CD spectroscopies. In water the peptide demonstrated a lack of regular secondary structure and existed as oligomers. Addition of the lipomimetic solvent, trifluoroethanol (TFE), led to the production of monomeric structured species. Analysis of NMR spectra of the hEGFRp indicated that an α-helix was present between residues M626 and R647. This observation was reinforced by solid state 2 H NMR studies in lipid bilayers which showed typical `Pake' spectra indicating axially symmetric motion. The helical region in hEGFRp commences four residues later than predicted via hydrophobicity profiles, and extends to include several charged arginine residues which would lie on the cytosolic side of the membrane. These observations provide the first evidence that the transmembrane α-helical region in EGFR may not only traverse the membrane but may continue to the cytosolic region near T654, an important phosphorylation site.

Conformational Preference of Two Toad Poison Bufadienolides, Cinobufagin and Bufotalin

The solution state conformations of pyran-2-one ring (E ring) of two toad poison bufadienolides, cinobufagin and bufotalin, were analyzed by using NOE experiments at low temperatures and molecular dynamics simulation study. The rotation of E ring of the two bufadienolides, was found to be affected by the 14β,15β-epoxy and 16β-acetoxy groups and to be restricted at low temperatures. In the experimental, cinobufagin and bufotalin were isolated from Ch'an Su by the new chromatographic methods using the hydrophobic gel sephadex LH-20 and HP-cellulofine as carriers.

Solution state conformation of an immunosuppressive cyclic dodecapeptide, cycloleonurinin

Abstract The cyclic dodecapeptide, cycloleonurinin, cyclo(-Gly-Pro-Thr-Gln-Tyr-Pro-Pro-Tyr-Tyr-Thr-Pro-Ala-), isolated from the fruits of Leonurus heterophyllus, showed potent immunosuppressive effect on human peripheral blood lymphocytes. The solution state conformation of cycloleonurinin was examined by high field NMR methods, distance geometry calculation and restrained energy minimization from NMR data. Calculation using 277 different initial structures led to a uniquely determined backbone conformation with a root mean square deviation value of 0.80 A. The backbone structure of cycloleonurinin consists of two β-turns, a β VI turn at Pro6-Pro7, and a β I turn at Pro11-Ala12. In addition to two transannular 4 → 1 backbone hydrogen bonds, which constructed two β-turns, two intramolecular hydrogen bonds between Tyr9-NH and Pro7-CO, and between Thr10-NH and Tyr8-CO, constructing γ-turns, and those between Thr3-NH and Tyr8-CO, and between Ala12-NH and Thr10-OH, were observed.

ChemInform Abstract: Cyclic Peptides from Higher Plants. Part 35. Conformation of Cyclic Heptapeptides: Solid and Solution State Conformation of Yunnanin A.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Crystal and solution state conformations of two taxoids, taxinine and taxinine B

Abstract Crystal and solution state conformations of two taxoids, taxinine and taxinine B, inhibiting the drug transport by P-glycoprotein in multidrug-resistant cells, were analyzed by X-ray crystallographic analysis and ROE experiments. This study demonstrated that in solid state, both taxinine and taxinine B took similar cage conformation in which A-ring and the cinnamoyl side chain at C-ring were specially very close to each other. These conformations were also observed in their solution conformations deduced by ROE correlations in CDCl3, Monte Carlo simulation using MM2∗ force field, and semiempirical molecular orbital calculation using PM3 method.

Conformation of cyclic heptapeptides: solid and solution state conformation of yunnanin A

The solid and solution state conformation of yunnamin A, a cyclic heptapeptide, cyclo(-Gly-Tyr-Gly-Pro-Phe-Pro-), isolated from the roots of Stellaria yunnanensis were studied. The X-ray diffraction studies showed that the crystal of yunnanin A [orthorhombic form from a ethanol-methanol mixture, a=11.754 (10), b=12.576 (7), c=30.731 (6) Å, space group P222 1 z=4] had three intramolecular hydrogen bonds forming one type II, one type II′ β-turns and a classical β-bulge unit with all trans amide bonds. The dominant solution conformation analyzed by NMR spectroscopy, Monte Carlo (MC) are restrained molecular dynamics (MD) calculations implemented in MacroModel/Batchmin (Ver. 4.5) was homologous to that in the solid state.

Proton and Carbon Chemical Shift Assignment and SolutionState Conformation of the Macrocyclic Ring in the Macrolide Antibiotic Tylosin in Aprotic Solvents

The 1H and 13C NMR spectra of the 16-membered macrolide antibiotic tylosin were unambiguously assigned. The solution conformation of the macrocyclic ring in aprotic solvents was investigated by a combination of NMR methods and force field calculations. The predominance of the conformer corresponding to the x-ray structure in aprotic solvents is proposed.