Flexibility of the pyranose ring in α- and β-D-glucoses

Conformational energies of α- and β-D -glucopyranoses were computed by varying all the ring bond angles and torsional angles using semiempirical potential functions. Solvent accessibility calculations were also performed to obtain a measure of solvent interaction. The results indicate that the ⁴C₁ (D ) chair is the most favored conformation, both by potential energy and solvent accessibility criteria. The ⁴C₁ (D ) chair conformation is also found to be somewhat flexible, being able to accommodate variations up to 10° in the ring torsional angles without appreciable change in energy. Observed solid-state conformations of these sugars and their derivatives lie in the minimum-energy region, suggesting that the substituents and crystal field forces play a minor role in influencing the pyranose ring conformation. Theory also predicts the variations in the ring torsional angles, i.e., CCCC < CCCO < CCOC, in agreement with the experimental results. The boat and twist-boat conformations are found to be at least 5 kcal mol^?1 higher in energy compared to the ⁴C₁ (D ) chair, suggesting that these forms are unlikely to be present in a polysaccharide chain. The ¹C₄ (D ) chair has energy intermediate between that of the ⁴C₁ (D ) chair and that of the twist-boat conformation. The calculated energy barrier between ⁴C₁ (D ) and ¹C₄ (D ) conformations is high—about 11 kcal mol^?1.     

Conformational analysis of the anomeric forms of kojibiose, nigerose, and maltose using MM3

Energy surfaces were computed for relative orientations of the relaxed pyranosyl rings of the two anomeric forms of kojibiose, nigerose, and maltose, the (1 → 2)-, (1 → 3)-- and (1 → 4)--linked -glucosyl disaccharides, respectively. Twenty-four combinations of starting conformations of the rotatable side-groups were considered for each disaccharide. Optimized structures were calculated using MM3 on a 20° grid spacing of the torsional angles about the glycosidic bonds. The energy surfaces of the six disaccharides were similar in many respects but differed in detail within the low-energy regions. The maps also illustrate the importance of the exo-anomeric effect and linkage type in determining the conformational flexibility of disaccharides. Torsional conformations of known crystal structures of maltosyl-containing molecules lie in a lower MM3 energy range than previously reported.     

DFT conformation and energies of amylose fragments at atomic resolution. Part 1: syn forms of α-maltotetraose

DFT optimization studies of 90 syn α-maltotetraose (DP-4) amylose fragments have been carried out at the B3LYP/6-311++G∗∗ level of theory. The DP-4 fragments studied include V-helix, tightly bent conformations, a boat, and a ¹C₄ conformer. The standard hydroxymethyl rotamers (gg, gt, tg) were examined at different locations in the residue sequence, and their influence on the bridge conformations ?/ψ values and conformer energy is described. Hydroxyl groups were considered to be homodromic, that is, they are either in the all clockwise, ‘c’, or all counterclockwise, ‘r’. Energy differences between conformations are examined in order to assess the stability of the different conformations and to identify the sources of energy that dictate amylose polymer formation. A small nearly cyclic compact structure is of low energy as one would expect when these flexible molecules are studied in vacuo. Many conformations in which the only differences are a single hydroxymethyl variation in the residue sequence show similar energies and bridge conformations, with trends being a result of the hydroxymethyl as well as hydroxyl orientation. In general the ‘c’ structures are of lower energy than the ‘r’ structures, although this is only true for the in vacuo state. The solvent dependence on conformational preference of several low-energy DP-4 structures was investigated via the continuum solvation method COSMO. These results suggest that the ‘r’ structures may be favored for fully solvated molecules.     

4-Membered metallodithiophosphinate rings - flat or puckered? A comparison of two crystal structures with computational and literature data

Two crystalline forms of (dithiodiphenylphosphinate)(phenyl)(triphenylphosphine)-palladium(II) (C₃₆H₃₀P₂PdS₂), one without solvent, the other containing THF (C₄H₈O), are obtained after reaction of sodium diphenyldithiophosphinate with (phenyl) (bis-triphenylphosphine) palladium(II) chloride and crystallisation from two different solvent mixtures. The molecular structures, as determined by single crystal X-ray diffraction, differ in the planarity of the 4-membered palladium dithiophosphinate rings. The experimental conformations have been compared to the conformations of four-membered metal-S₂P rings reported in the Cambridge Structural Database. A flat conformation is more common than a puckered one. DFT calculations at the B3LYP level of theory indicate that the flat conformation of a model metallodithiophosphinate ring is very slightly lower in energy (1.2 kcal/mol) than the puckered conformation.     

Conformational Aspects of Differences in Requirements for Oxytocin and Vasopressin Receptors

Abstract

Conformational energy calculations were carried out on three non-peptide antagonists of oxytocin and vasopressin: penicilide (compound 1; selective for oxytocin receptors), 1- {1-[4-(3-acetylaminopropoxy (benzoyl]-4-piperidyl}-3,4-dihydro-2(1H)-quinoline (compound 2; selective for vasopressin V₁ receptors) and 5-dimethylamino-1-{(2-methylbenzylamino)-benzoyl}-2,3,4,5–tetrahydro-1H-benzapine (compound 3; selective for vasopressin V₂ receptors). The obtained low-energy conformations of compound 1 were compared with low-energy conformations of oxytocin (OT) and low-energy conformations of compounds 2 and 3 were compared with low-energy conformations of arginine vasopressin (AVP). It was found that the affinity of the non-peptide antagonists and their selectivity for vasopressin and oxytocin receptors is probably connected with mimicking the aromatic rings of the Tyr² and the Phe³ residues of AVP in the case of compounds 2 and 3 and with mimicking the Tyr² residue and the Ile³ or Leu⁸ residues of OT by the outer benzene ring and the isobutyl group of compound 1. Application of the results in the design of more potent non-peptide antagonists of OT and VP is also discussed.     

Molecular dynamics study of iduronate ring conformation

Molecular dynamics (MD) simulations of the conformation of the iduronate ring in a methyl glycoside and as the central residue in a trisaccharide have been carried out. Separate simulations were carried out with initial ¹C₄, ²S₀, and ⁴C₁ iduronate ring conformations. Simulations were followed by observing the time development of the Cremer–Pople ring puckering parameters θ,?₂. Starting with chair geometries gave trajectories showing only ring oscillations close to the initial geometry. Simulations were performed with a ²S₀ starting geometry using explicit water and in vacuum with dielectric constants (ε) of 1 and 80, as well as with distance-dependent dielectric functions of 2r and 4r. In both the explicit water simulation and the vacuum (ε = 80) simulations, extensive pseudorotational motion was observed in which boat and twist-boat ring conformers interconvert. The overall range of ?₂2 variation in the trisaccharide was about half of that observed in the methyl glycoside. The Haasnoot procedure for calculating H-H coupling constants in saccharides was applied to structures obtained from MD trajectories. Using MD time averaged couplings along with experimental data allowed the relative fractions of chair and boat/twist-boat forms to be derived. © 1993 John Wiley & Sons, Inc.     

Systematic conformational search for the branching point of amylopectin

A systematic modelling for the branching point of amylopectin, on the basis of the double-helical structure proposed for amylose polymorphs was performed. A ‘several steps’ approach was used with increasing sophistication in the refinement, combining the use of geometrical criteria and molecular mechanics calculations. This modelling leads to four groups of solutions which were compared with those existing for amylose and the related oligomers. The most stable conformations provide a minimum of deformations for the (1–4) linkages adjacent to the branching point. The conformation of minimum energy roughly corresponds to the proposal of Imberty and Perez and includes an (1–6) configuration compatible with the well-known calculated maps. The other possible solutions are discussed in terms of deformations for the glucopyranose rings and of unusual conformation domains for the (1–6) linkage.     

Several transition states from C1 to skew conformations of β-d-glucopyranose

The interconversion pathways in the ring distortion of β-d-glucopyranose were investigated using density functional calculations. We examined the energies of several conformers of β-d-glucopyranose and tried to obtain the transition-state conformation and determine the pathway between a ⁴C₁ chair and some distorted ring conformers. The results showed that two E₃/²H₃ conformations and one E₃/⁴H₃ conformation were transition states in such ring puckering. The transition state with the lowest energy conformation is the E₃/²H₃ ring conformation with the side-chain conformation of r-ggG⁺. Intrinsic reaction coordinate calculations indicated that the E₃/²H₃ conformation with the lowest conformational energy is a transition state of the ring interconversion path between the conformations of ⁴C₁ and ²S_O/B_3,O. The energy barrier of this interconversion was 6.13 kcal/mol. As far as we know, this is the first example of finding pathways for an interconversion of glucopyranose ring puckering at the level of a quantum chemical calculation.     

Conformational studies of per-O-trimethylsilyl derivatives of D-fructoses and oligosaccharides containing β-D-fructofuranose residues by 220- and 300-MHz P.M.R. spectroscopy

The interpretation of 220- and 300-MHz P.M.R. spectra and the accurate chemical shifts and coupling constants of a number of per-O-trimethylsilyl-(TMS-) D-fructose derivatives and TMS-oligosaccharides containing β-D-fructofuranose residues are presented. On the basis of calculations with an adapted Karplus equation it is concluded that TMS-α- and -β-D-fructopyranose occur in the ²C₅(D) chair conformation whereas the D-glucopyranose rings in the oligosaccharides adopt the usual ⁴C₁(D) chair conformation. The structure of the latter units is very similar to that of TMS-α-_D-glucopyranose. The ⁴E(D) envelope and ⁴T₅(D) twist are the principal conformations of the D-fructofuranose rings. The conformation of the furanose ring depends on the number and kind of monosaccharide units attached thereto. The calculated, preferred conformation of the C-5-CH₂OTMS group of the D-fructofuranose moieties correlates with the time-averaged displacement of C-4 above the plane of C-2, C-3, and O-5.     

Conformational energy calculations of enzyme-substrate complexes of lysozyme. I. Energy minimization of monosaccharide and oligosaccharide inhibitors and substrates of lysozyme

Conformational energy calculations were performed on monosaccharide and oligosaccharide inhibitors and substrates of lysozyme to examine the preferred conformations of these molecules. A grid-search method was used to locate all of the low-energy conformational regions for N-acetyl-β-D -glycosamine (NAG), and energy minimization was then carried out in each of these regions. Three stable positions for the N-acetyl group have ben located, in two of which the plane of the amide unit is normal to the mean plane of the pyranosyl ring. Nine local energy minima were located for the —CH₂OH group. The positions of the two vicinal cis —OH groups are determined predominantly by interactions with either the —CH₂OH or the N-acetyl group. The most stable conformations of β-N-acetylmuramic acid (NAM) were determined from the study of the low-energy conformations of NAG. In the two stable orientations for the D -lactic acid side chain, the O—C—C′ plane (C′ being the carbon atom of the terminal carboxyl group) was found to be normal to the mean plane of the pyranosyl ring. The low-energy positions for the COOH group of NAM are determined mainly by interactions with neighboring groups. The conformational preferences of the α-anomers of NAG and NAM were also explored. The calculated conformation of the N-acetyl group for α-NAG was quite close to that determined by X-ray analysis. Two of the three lowest energy conformations of α-NAM are similar to the corresponding conformations of the β-anomer. A third low-energy structure, which has a hydrogen bond from the NH of the N-acetyl group to the C?O of the lactic acid group, corresponds very closely to the X-ray structure of this molecule. The preferred conformations of the disaccharides NAG–NAG, NAM–NAG and NAG–NAM were also investigated. Two preferred orientations of the reducing pyranosyl ring relative to the nonreducing ring were found for all of these disaccharides, both of which are close to the extended conformation. In one of these conformations, a hydrogen bond can form between the OH group attached to C₃ of the reducing sugar and the ring oxygen of the preceding residue. Each conformation can be stabilized further by a hydrogen bond between the CH₂OH (donor) of residue i + 1 and the C?O of residue i (acceptor). The interactions that determine conformations for all oligosaccharides containing both NAG and NAM are shown to be exclusively intraresidue and nearest neighbor interactions, so that it is possible to predict all stable conformations of oligosaccharides containing NAG and NAM in any sequence.     

Nuclear magnetic resonance study of ring conformations of cyclic tetradepsipeptide AM-toxins and related peptides

Cyclic tetradepsipeptides, AM-toxin I and II, are the host-specific phytotoxins of Alternaria mali. In order to elucidate conformation-toxicity relationships, we analyzed the 270-MHz proton nmr spectra of AM-toxins and hydrogenated analogs, (D -Ala²)AM-toxin I (toxic) and (L -Ala²)AM-toxin I (not toxic), in (C²H₃)₂SO. These cyclic tetradepsipeptides do not contain N-substituted amino acid residues, and all the peptide and ester groups have been found to be transoid. Two conformers with very unequal populations have been found for AM-toxin I and II; the C^β?C^α? C?O conformations of the Dha² residues are nonplanar S-trans in the major conformer and nonplanar S-cis in the minor conformer. Only one ring conformation has been found for each of (L -Ala²) and (D -Ala²)AM-toxin I. (L -Ala²)AM-toxin I takes a C₄-type ring conformation; all the C?O groups and C^α-H bonds are oriented to the same side of the ring. (D -Ala²)AM-toxin I takes a new ring conformation; the side chain and C?O group of the L -Amp¹ residue are oriented to the same side of the ring. This new conformation is also found for the major conformers of AM-toxin I and II and thus appears to be required for the toxicity. The ring conformations of Tyr(OCH₃)¹-bearing analog tetradepsipeptides have been found to be much the same as those of Amp¹-bearing depsipeptides. Furthermore, on the basis of the two distinct conformations of (D -Ala²) and (L -Ala²)AM-toxin I, an empirical rule is proposed for the stable ring conformations of cyclic tetra-D ,L -peptides, not containing N-substituted amino acid residues.     

Altered product specificity of a cyclodextrin glycosyltransferase by molecular imprinting with cyclomaltododecaose

Cyclodextrin glycosyltransferases (CGTases), members of glycoside hydrolase family 13, catalyze the conversion of amylose to cyclodextrins (CDs), circular α‐(1,4)‐linked glucopyranose oligosaccharides of different ring sizes. The CD containing 12 α‐D‐glucopyranose residues was preferentially synthesized by molecular imprinting of CGTase from Paenibacillus sp. A11 with cyclomaltododecaose (CD₁₂) as the template molecule. The imprinted CGTase was stabilized by cross‐linking of the derivatized protein. A high proportion of CD₁₂ and larger CDs was obtained with the imprinted enzyme in an aqueous medium. The molecular imprinted CGTase showed an increased catalytic efficiency of the CD₁₂‐forming cyclization reaction, while decreased k_cat/K_m values of the reverse ring‐opening reaction were observed. The maximum yield of CD₁₂ was obtained when the imprinted CGTase was reacted with amylose at 40°C for 30 min. Molecular imprinting proved to be an effective means toward increase in the yield of large‐ring CDs of a specific size in the biocatalytic production of these interesting novel host compounds for molecular encapsulations. Copyright © 2010 John Wiley & Sons, Ltd.     

Modelling of β-d-glucopyranose ring distortion in different force fields: a metadynamics study

Modelling of carbohydrate conformations is a challenging task for force field developers. Three carbohydrate force fields, namely GLYCAM06, GROMOS 45a4 and OPLS were evaluated. Free energies of different ring conformations of β-d-glucopyranose were calculated using metadynamics in vacuum as well as in explicitly modelled water. All three force fields model the ⁴C₁ conformation as the most stable by at least 6 kJ/mol, as compared to other conformations. Interconversion from the ⁴C₁ to any other conformation is associated with a barrier of no lower than 26 kJ/mol. The free energy surface calculated in the GLYCAM06 force field is in remarkably good agreement with the recent Car-Parrinello metadynamics study. The effect of a water environment is relatively low and analogous in all tested force fields. Namely, the presence of water stabilizes the upper-left (^3,OB) versus bottom-right (B_3,O) area of Stoddard’s plot, relative to the situation in vacuum. Comparison of free and potential surfaces is also provided for vacuum calculations.     

Investigating proline puckering states in diproline segments in proteins

In the current study, the puckering states of the Proline ring occurring in diproline segments (^LPro‐^LPro) in proteins has been investigated with a segregation made on the basis of cis and trans states for the Pro‐Pro peptide bond and the conformational states for the diproline segment to investigate the effects of conformation of the diproline segment on the corresponding puckering state of the Proline ring in the segment if any. The value of the endocyclic ring torsional angles of the pyrrolidine ring has been used for calculating and visualizing various puckering states using a proposed new sign convention (+/?) nomenclature. The results have been compared to that obtained in a previous study on peptides from this group. In this study, quite interestingly, the Planar (G) conformation that was present in 14.3% of the cases in peptides, appears to be nearly a rare conformation in the case of proteins (1.9%). The present study indicates that the (C^γ‐exo/C^γ‐exo), (C^γ‐exo/Twisted C^γ‐exo‐C^β‐endo) and (Twisted C^γ‐endo‐C^β‐exo/Twisted C^γ‐endo‐C^β‐exo) categories are the most preferred combinations. For Proline rings in proteins, the states C^γ‐exo, Twisted C^γ‐exo‐C^β‐endo and Twisted C^γ‐endo‐C^β‐exo are the most preferred states. Within diproline segments, the pyrrolidine ring conformations do not show a strong co‐relation to the backbone conformation in which they are observed. It is likely that five‐membered rings have a considerable plasticity of structure and are readily deformed to accommodate a variety of energetically preferred backbone conformations. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 605–610, 2013.     

Strukturanalyse der methyl-2,3,6-tridesoxy-2-C-[2-hydroxy-1,1-(Äthylendithio)Äthyl]-α-l-threo-hexopyranosid-4-ulo-22,4-pyranose

Methyl 2,3,6-trideoxy-2-C-[2-hydroxy-1,1-(ethylenedithio)ethyl]-α-l-threo-hexopyranosid-4-ulo-2²,4-pyranose (1) crystallizes in a rhombic space group P2₁2₁2₁ with four molecules in the elementary unit. The structure was refined to an R-value of 0.057. The aldopyranose ring adopts a ¹C₄ conformation with an axial side-chain forming a hemiacetal ring to the keto group at C-4. Both six-membered rings connected in the 2,7-dioxabicyclo[3.3.1]nonane system differ only slightly from the ¹C₄ chair conformation. The spirocyclic dithiolane ring adopts a nearly ideal envelope form with a deviation of C-21 from the plane S-1-C-7-S-2-C-22. The dihedral angle O-5-C-1 O-1-C-11 of 59.1° is an agreement with the exo-anomeric effect.     

Synthesis and X-ray structure of a C5-C4-linked glucofuranose-oxazolidin-2-one

The formation of (4R)-4-carbamoyl-4-[(4R)-3-O-benzyl-1,2-O-isopropylidene-β-l-threofuranos-4-C-yl]-oxazolidin-2-one instead of expected imidazolidin-2,4-dione (hydantoin) derivative from 5-amino-5-cyano-5-deoxy-3-O-benzyl-1,2-O-isopropylidene-α-d-glucofuranose or 3-O-benzyl-1,2-O-isopropylidene-α-d-xylo-hexofuranos-5-ulose under Bucherer-Bergs reaction conditions is reported. Single crystal X-ray diffraction data revealed that ³T₄ is the prefered conformation for the furanose ring, while E₂ and ²T₁ conformations are adopted by the 1,3-dioxolane and 2-oxazolidinone five-membered rings, respectively.     

A systematic evaluation of different hydrogen bonding patterns in unsymmetrical 1,n′-disubstituted ferrocenoyl peptides

The synthesis and spectroscopic characterization of 21 l,l′-disubstituted ferrocenoyl peptides of the general formula [Fe(C₅H₄-CO-Aal-OR) (C₅H₄-CO-Aa2-OR′)] is reported, with Aal and Aa2 being different amino acids. The one-pot synthesis from activated ferrocene-l,l′-dicarboxylic acid and two different amino acid esters gives the unsymmetrical ferrocenoyl peptides in yields between 27% and 42%, which can be easily separated from their symmetrical byproducts by column chromatography. All new compounds are comprehensively characterized by mass spectrometry (El and FAB, including high-resolution EI-MS), ¹H and ¹³C NMR, and UV/Vis spectroscopy. CD spectroscopy in conjunction with ¹H NMR is used to elucidate the solution structures. Using the achiral glycine (Gly) as Aal permits to determine qualitatively the structure-determining influence of the different amino acids Aa2. Helically chiral structures in ferrocene amino acids in this study are stabilized by hydrogen bonds. If one hydrogen bond partner is systematically moved away by the introduction of methylene groups, then indeed the strength of the hydrogen bond decreases as indicated by ¹H NMR chemical shifts of the amide protons and the strength of characteristic CD bands. As proline (Pro) is the only naturally accuring secondary amino acid it cannot contribute any amide proton to intra-strand hydrogen bonding. DFT calculations on the compound [Fe(C₅H₄-CO-Gly-OMe)(C₅H₄-CO-Pro-OMe)] with one achiral and one secondary amino acid were therefore performed to quantify the more subtle influence of the relative orientations of the ferrocene carbonyl groups and the cis-/trans-conformation of both amide bonds. Not unexpectedly, the conformations with both amide bonds in cis orientation are highest in energy. Surprisingly, the calculations suggest the presence of a low-energy conformation with a non-classical hydrogen bond between the proline ester carbonyl oxygen and a glycine H_α atom. However, a second conformation with no apparent intra-strand contacts but optimal positioning of all relevant groups is similar in energy. Although two conformations were observed in solution for this compound, the experimental data did not permit to assign those two conformations.     

Conformational flexibility in the molecular structure of rotenone, a naturally occurring insecticide

The crystal and molecular structure of rotenone, a naturally occurring insecticide with mitochondrial and mitotic spindle inhibitory properties, was determined by direct methods. The crystals were orthorhombic, space group, P2_I2_I2_I with two molecules in the asymmetric unit; a = 8.413 (1) Å, b = 19.840(1), c = 23.581(1), V = 3936 ų, Z = 8. The structure was refined by least-squares methods to a final R = 0.067. The two molecules in the asymmetric unit have different conformations about the junction between the nonaromatic rings B and C. Ring B is in a sofa conformation in both molecules, with a slight distortion toward a half-chair in I, but with C8 and C8′ on opposite sides of the planar part of the rings. This difference in conformation results in I having an extended (linear) shape while II is V-shaped. The more elongated conformation of the molecule (I) has not been reported in previous studies. Ring C also has opposite conformations in the two molecules. The angle between the planes formed by rings A and D in molecule I is 64.3°, while in molecule II it is 88.3°. Molecular mechanics techniques were used to determine the energy of the two conformations. These calculations, at room temperature, predict molecule II to be the more stable conformer. The highly flexible site in the B/C ring junction is also chemically very reactive. This flexibility and reactivity are further discussed in terms of rotenone's inhibitory activities.     

Amylose chain behavior in an interacting context II. Molecular modeling of a maltopentaose fragment in the barley α‐amylase catalytic site

In the first paper of this series, the tools necessary to evaluate the consequences of glucopyranose ring deformations in terms of glycosidic torsion angle shifts, and amylose chain propagation have been created. In this second paper, the modeling of amylose fragments into the catalytic region of barley α‐amylase has been performed by a systematic approach. From the crystal data of the acarbose/amylase complex, maltotriose and maltopentaose fragments have been docked in the catalytic cleft. It has been found that for the trisaccharide, no substrate ring deformation is needed to respect stacking interactions (with Y51 and W206) characteristic of the substrate binding. However, for the pentasaccharide the deformations of rings A and C (from chair { C } toward half‐chair { H2 } and skew { S4 }, respectively) are essential conditions to fit this amylose fragment into the narrow catalytic site. Within five contiguous binding subsites, all important enzyme residues have been listed, which is of great importance for the understanding of the cleavage mechanism or any further biochemical modification. The best energy docking solution that was found is consistent with experimental data. © 1999 John Wiley & Sons, Inc. Biopoly 49: 107–119, 1999