Application of ab initio molecular-orbital calculations to the structural moieties of carbohydrates. Part VI

Ab initio RHF/4–31G molecular-orbital calculations have been conducted on methoxymethyl formate and methoxymethyl acetate as models for examining the anomeric effect and stereochemistry of 1-O-acetylglycopyranoses. The results indicate that, as with the methyl glycopyranosides, the α-⁴C₁(D) configurations are more stable than the β-⁴C₁(D), except that the energy difference is more dependent on the disposition about the glycosidic bond. The lowest-energy conformations occur with glycosidic torsion-angles of ?  180°, where the anomeric energy is about 4 kcal/mol. There is a secondary energy-minimum at ?  90°, for which the anomeric energy is less, about 2 kcal/mol. This orientation corresponds to the conformation most commonly observed in the crystal structures of peracetylated glycopyranoses. Small differences in the CO single-bond lengths, which are observed experimentally in both the α and β anomers, are reproduced by the theoretical calculations.     

GlcNAc-Thiazoline conformations

The title compound, a powerful inhibitor of retaining N-acetylhexosaminidases, can move freely among three pyranose solution conformations of similar energy—two twist boats and the ⁴C₁ chair—as revealed by NMR, calculational, and crystallographic studies. It binds in the enzyme active site only in the pseudo-⁴C₁ conformation, however, in which it most closely resembles the hypothetical bound substrate transition state, a ⁴E sofa that is approximately trigonal bipyramidal at the anomeric carbon.     

Theoretical studies on the conformations of aldohexopyranose pentaacetates

The net charges on various atoms of aldohexopyranose pentaacetates were computed by using the MO-LCAO method of Del Re for σ-charges and the Hückel MO method for π-charges. The potential and free energies of sixteen aldohexopyranose pentaacetates in the C1(D) and 1C(D) conformations were estimated. Minimization of the energies of these conformations was studied by suitably tilting the axial CC and CO bonds. As with the free sugars, considerable release of strain is achieved when tilts of 4.5 and 2° are given to the axial CH₂OAc and the axial OAc groups, respectively, involved in the Hassel—Ottar effect in the 1C(D) conformations. In the case of C1(D) conformations, the ideal models have the minimum energy even when the acetate groups are involved in syn-axial interactions, indicating that strain induced by axial acetate groups is less than that of axial hydroxyl groups. The calculated free-energies agree well with the experimental values after adding a value of 0.9 kcal.mole^-1 for the anomeric effect of the acetoxyl group. The free-energy calculations also predict that α-D-idohexopyranose pentaacetate and α-D-altrose pentaacetate favour the C1(D) conformation and β-D-idose pentaacetate a C1?1C equilibrium in solution, in agreement with n.m.r. studies.     

The conformation of tetrafluorinated methyl galactoside anomers: crystallographic and NMR studies

The first single-crystal X-ray diffraction study of tetrafluorinated monosaccharide derivatives is presented. Both α- and β-methyl 2,3-dideoxy-2,2,3,3-tetrafluoro-d-galactopyranoside anomers adopt the ⁴C₁ conformation. The values for the C1–O1 and C1–O5 bond lengths and the O5–C1–O1–CH₃ dihedral angles are in line with what can be expected from the anomeric and exo-anomeric effects. The chair conformations are slightly distorted, presumably due to repulsion between 1,3-diaxial C–O and C–F bonds. The asymmetric unit of both compounds contains up to three independent molecules, which differ in the conformation of the hydroxymethyl group (including in one case a ‘forbidden’ gg rotamer). The molecular packing of the β-anomer shows a clear segregation between fluorinated and hydrophilic domains, while for the α-anomer the regions of fluorine segregation are broken by interleafing of OMe groups. There is one close OH?F contact, which is likely to arise from the crystal packing. NMR studies show that the two anomers also adopt a ⁴C₁ conformation in solution (D₂O, CDCl₃).     

Einfluß der syn-1,3-diaxialen wechselwirkung auf konformationsgleichgewichte der 2,4-diamino-2,4-didesoxy-α-d-idopyranose

Conformational equilibria of derivatives of 2,4-diamino-2,4-dideoxy-α-d-idopyranose are investigated. In the case of methyl 2,4-diacetamido-3,6-di-O-acetyl-2,4-dideoxy-α-d-idopyranoside, the proportion of the ¹C₄ conformation is between 7 and 44%, depending upon the solvent, and increases with increasing polarity of the solvent. Methyl 2,4-di(N-acetyl-N-acylamino)-3,6-di-O-acyl-2,4-dideoxy-α-d-idopyranosides show such strong steric 1,3-diaxial interaction that the proportion of the ¹C₄ conformation is 93%. Methyl 2,4-diamino-2,4-dideoxy-α-d-idopyranoside and its bis(ammonium) salt show strong 1,3-diaxial interactions of polar nature, resulting in an increase of the ¹C₄ conformation up to 74% and 84%, respectively.     

Computational analyses of the conformational itinerary along the reaction pathway of GH94 cellobiose phosphorylase

GH94 cellobiose phosphorylase (CBP) catalyzes the phosphorolysis of cellobiose into α-d-glucose 1-phosphate (G1P) and d-glucose with inversion of anomeric configuration. The complex crystal structure of CBP from Cellvibrio gilvus had previously been determined; glycerol, glucose, and phosphate are bound to subsites −1, +1, and the anion binding site, respectively. We performed computational analyses to elucidate the conformational itinerary along the reaction pathway of this enzyme. autodock was used to dock cellobiose with its glycon glucosyl residue in various conformations and with its aglycon glucosyl residue in the low-energy ⁴C₁ conformer. An oxocarbenium ion-like glucose molecule mimicking the transition state was also docked. Based on the clustering analysis, docked energies, and comparison with the crystallographic ligands, we conclude that the reaction proceeds from ¹S₃ as the pre-transition state conformer (Michaelis complex) via E₃ as the transition state candidate to ⁴C₁ as the G1P product conformer. The predicted reaction pathway of the inverting phosphorylase is similar to that proposed for the first-half glycosylation reaction of retaining cellulases, but is different from those for inverting cellulases. NAMD was used to simulate molecular dynamics of the enzyme. The ¹S₃ pre-transition state conformer is highly stable compared with other conformers, and a conformational change from ⁴C₁ to ^1,4B was observed.     

Conformations of methyl 3,4-dideoxy-DL-glyc-3-enopyranosides

The conformational equilibrium (°H₁ ?¹H°) has been established for 26 diastereoisomeric methyl 3,4-dideoxy-DL-glyc-3-enopyranosides on the basis of the coupling constant J_1,2. The position of equilibrium depends on the interplay of steric and polar factors. The concept of the allylic effect is useful in explaining some conformational phenomena.     

Proton and carbon-13 nuclear magnetic resonance studies on methyl (methyl d-galactosid)uronates and their per-O-acetyl derivatives

The ¹H- and ¹³C-n.m.r. spectra of the anomeric methyl (methyl d-galactosid)uronates, as well as the ¹H-n.m.r. spectra of their acetyl derivatives, were analyzed. The spectra of the unacetylated d-galactopyranosiduronates showed good correlation with those of the corresponding anomeric d-galactopyranuronic acids and their methyl esters, and with those of the anomeric methyl d-galactopyranosides. From the values of the chemical shifts and coupling constants, it was concluded that the anomeric methyl (methyl d-galactopyranosid)uronates and their corresponding peracetates are in the ⁴C₁(d) conformation. The chemical shifts in the ¹³C-n.m.r. spectra show good correlation with those of the methyl d-galactosides. The signals of the furanose derivatives appear at fields lower than those of the corresponding pyranose compounds.     

The strucrure of trans-O-β-D-glucopyranosyl methyl acetoacetate,and the interpretation of its optical rotations

Crystal-structure determination of trans-O-β-D-glucopyranosyl methyl acetoacetate, C₁₁H₁₈O₈, m.p. 186°, confirmed the trans orientation deduced previously from physical properties. The conformation of the D-glucopyranosyl group is ⁴C₁, although the most symmetrical chair-conformer is actually ³C_o. The glycosidic link is sc, with a CO anomeric bond of 1.428 Å (142.8 pm), i.e. longer than is normal in methyl β-glycopyranosides. All of the hydrogen bonding is intermolecular. The unusual optical rotations in solution can be interpreted in terms of rotameric populations that are derived from the solid-state conformers and are stabilized by intramolecular or solvent hydrogen-bonding.     

A stereochemical model for phospholipids: I. Conformational energy refinement and molecular packing of l-α-Dipalmitoyl lecithin (DPL)

The preferred conformations of L-α-dipalmitoyl-lecithin (DPL) have been refined using a steepest descent procedure throughout non-bonded potential energy calculations. The results indicate that energy differences between the conformers is very low and the energy parameters are quite constant around the minimum, suggesting a large degree of flexibility of this molecule.The molecular packing energy calculations have been performed by separating the two hydrocarbon chains from the polar head groups of the molecule. From the energy parameters for the packing of the aliphatic chains it results that for distances between adjacent chains up to 4·4 Å the intermolecular forces allow the maximum degree of freedom. This suggests that hydrocarbon chains do not play the main role in the packing process of DPL molecule. Therefore the energy parameters of the polar segment have been calculated, assuming that the C₂ asymmetric carbon atom represents the points of the hexagonal lattice and the rotation centre for each molecule. For the internal symmetry of this segment of the molecule two non-equivalent conformers have been selected over all sets of allowed conformations (the GGG and GGG¹ for the α₂, α₃ and α₅ torsion angles). The energy packing calculation has been carried out for two independent sets of data, with and without the electrostatic contributions. In the first case a unique topological situation is allowed with the P-N dipole lying parallel to the lattice plane. In the second case different situations including that with the P-N dipole lying orthogonal to the plane are allowed. These data are discussed in relation to different physical conditions.     

Theoretical studies on the conformations of methyl glycopyranosides

The σ-charges on various atoms of methyl glycosides have been computed by using the MO-LCAO method of Del Re. The potential and free energies of methyl aldohexopyranosides and methyl aldopentopyranosides in their C1(d) and 1C(d) conformations have been calculated. Minimization of the energies of these conformations has been studied by suitably tilting the axial C-C and C-O bonds. Considerable release of strain is achieved when tilts of 4.5 and 3° are given to the axial hydroxymethyl and hydroxyl groups, respectively, that are involved in Hassel-Ottar effect. A tilt of 3° is also found necessary for the axial OMe group involved in the Hassel-Ottar effect. The calculated free-energy values are in accord with experimental ones, after adding a value of 0.8 kcal.mole^?1 for the anomeric effect of -OMe group. These studies predict that all of the methyl aldohexopyranosides, except methyl α-d- and methyl β-d-idopyranosides, favour the C1 conformation. On the other hand, the energy calculations also predict that, of the eight methyl aldopentopyranosides studied, only methyl α-d- and methyl β-d-xylopyranosides and methyl α-d -ribopyranoside favour the C1(d) conformation; for the other pentopyranosides, considerable amounts of both C1(d) and 1C(d) conformations are present in the equilibrium mixture. The calculated values of the percentage of α-anomer present in the equilibrium mixture agree fairly well with those obtained experimentally.     

Konformationen von 1,2,3,4-tetra-O-benzoyl-β-D-xylopyranose, 1,5-anhydro-2,3,4-tri-O-benzoylxylitol und 1,5-anhydro-2,3,4-tri-O-benzoylribitol

1,2,3,4-Tetra-O-benzoyl-β-D-xylopyranose (1) has been shown to exist, in acetone-d₆ at room temperature, as a 1:1 mixture of the ¹C₄ and ⁴C₁ conformers, but it crystallizes in the all-axial ¹C₄ form with two molecules in the asymmetric unit (monoclinic, P2₁). 1,5-Anhydro-2,3,4-tri-O-benzoylxylitol, which compared to 1 lacks the anomeric effect, shows in solution a ratio of the ⁴C₁ to ¹C₄ conformers of about 81:19 and crystallizes in the all-equatorial ⁴C₁ conformation (triclinic, P$\text{1}$). 1,5-Anhydro-2,3,4-tri-O-benzoylribitol adopts in solution the ⁴C₁ form to the extent of about 54% and also crystallizes in this conformation with two equatorial benzoyloxy groups (monoclinic, P2₁/c).     

Factors affecting molecular packing in mixed lipid monolayers and bilayers

The nature of the molecular interactions and the factors determining molecular packing in mixed phospholipid/glyceride monolayers and bilayers were investigated by monolayer and nuclear magnetic resonance (NMR) techniques. Force-area curves were obtained at various temperatures for monolayers, at the air-water interface, of synthetic lecithins and a phosphatidyl ethanolamine mixed with di- and triglycerides in different molar ratios. The linewidths of peaks in the high resolution NMR spectra of lecithin/glyceride co-dispersions in excess water at different temperatures were used to obtain information about molecular mobilities.It was found that the molecular packing in mixed lipid monolayers and bilayers is determined by the following factors: (1) Whether lipid chains are above or below their melting point (T_C). (2) The difference between experimental temperature and T_C: the larger the difference, the smaller the effect of one component on the other. (3) The degree of similarity of the chains of the components; this influences the degree of cooperativity of chain motions and the degree of mixing of the components. (4) The nature, orientation, mutual interaction and degree of hydration of the polar groups.It is shown that mean molecular area does not always reflect the state of chain motions in lipid films, because of heterogeneity of motion and structure along the molecules. Cooperativity of motion may reduce steric requirements; other effects which are of particular importance for lecithins are interactions of zwitterions, and the influence of polar group hydration.     

Conformational characteristics of polypeptides containing isolated L-proline residues with cis peptide bonds

The conformational characteristics of the peptide sequence X-l-Pro, where X  Gly or l-Ala and the peptide bond joining X and l-Pro is cis, are evaluated. Semi-empirical potential functions are used to estimate the contributions to the conformational energy made by the non-bonded van der Waals' and electrostatic interactions and the intrinsic torsional potentials about the NC^a and C^aC′ bonds. Rotations φ₁ and ψ₁ about the NC^a and C^aC′ bonds in residue X and rotation ψ₂ about the C^aC′ bond in l-Pro are permitted, while the angle of rotation φ₂ about the NC^a bond in l-Pro is fixed at 120 ° by the pyrrolidine ring. The presence of the cis peptide bond connecting X and l-Pro renders the backbone rotations φ₁, ψ₁ in X dependent upon the rotation ψ₂ about the C^aC′ bond in l-Pro. (Interdependence of rotations in neighboring residues joined by a cis peptide bond was previously observed in l-alanine oligomers.) The number of energetically allowed conformations for the Gly and l-Ala residues preceding a cis peptide bond l-Pro residue are found to be substantially reduced from those permitted when the peptide bond is trans or when l-Pro is replaced by an amino acid residue. On the other hand, ψ₂ = 100 to 160 ° (cis′) and 300 to 0 ° (trans′) are found to be the lowest energy conformations of the l-Pro residue irrespective of the cis or trans conformation of the X-l-Pro peptide bond.     

Der einfluss des anomeren effektes auf furanosekonformationen. Röntgenstrukturanalyse fünf isomerer methyl-3,6-anhydrohexofuranoside

X-Ray crystallographic analysis of five isomeric methyl 3,6-anhydrohexofuranosides, methyl 3,6-anhydro-β-d-glucofuranoside (1), methyl 3,6-anhydro-α-l-idofuranoside (2), methyl 3,6-anhydro-β-d-mannofuranoside (3), methyl 3,6-anhydro-α-d-glucofuranoside (5), and methyl 3,6-anhydro-α-d-mannofuranoside (7), showed that the anomeric effect determines the conformation of the furanoid ring, which resulted in the quasi-axial orientation of the aglycon in all cases. Thus, 2 adopts an almost ideal E₂ conformation, whereas 1 and 3 having the same R configuration at the anomeric center showed conformations of the furanoid ring intermediate between E₂ and ¹T₂. Of the anomers 5 and 7 having an S configuration at C-1, 7 showed a related but opposite geometry, intermediate between ²E and ²T₁, and 5 had a ^oT₁ conformation, slightly distorted into ^oE. The anhydroring of all compounds showed a C-6 endo orientation, with the exception of 7, in which C-6 is exo oriented. These results from compounds in the solid state were compared with the conformations of the same compounds in solution, as deduced by ¹H-n.m.r. spectroscopy.     

Zn2+, Mg2+, and H+ binding to d-fructose 1,6-bisphosphate studied by 31P and 1H NMR

The anomeric composition and mutarotation rates of fructose 1,6-bisphosphate were determined in the presence of 100 mm KCl at pH 7.0 by ³¹P NMR. At 23 and 37 °C the solution contains (15 ± 1)% of the α anomer. The anomeric rate constants at 37 °C are (4.2 ± 0.4) s^?1 for the β → α anomerization and (14.9 ± 0.5) s^?1 for the reverse reaction. A D₂O effect between 2.1 and 2.6 was found. From acid base titration curves it appeared that the pK values of the phosphate groups range from 5.8 to 6.0. Mg²⁺ and Zn²⁺ bind preferentially to the 1-phosphate in the α-anomeric position. Zn²⁺ has a higher affinity for this phosphate group than Mg²⁺ has. At increasing pH the fraction α anomer decreases slightly. At increasing Mg²⁺/fructose 1,6-bisphosphate ratios the fraction α anomer increases till 19% at a ratio of 20. Proton and probably Mg²⁺ binding decreases the anomerization rate. The time-averaged preferred orientation of the 1-phosphate along the C₁O₁ bond of the α conformer is strongly pH dependent, gauche rotamers being predominant at pH 9.4. In the presence of divalent cations the orientation is biased toward trans. A mechanistic model is proposed to explain the Zn²⁺, Mg²⁺, and pH-dependent behavior of the gluconeogenic enzyme fructose 1,6-bisphosphatase.     

X-Ray crystal and molecular structure of 1,2,3,5-tetra-O-acetyl-4-deoxy-4-C-[(S)-ethylphosphinyl]-α-d-ribofuranose,and conformations of aldopentofuranose analogs having phosphorus in the hemiacetal ring

X-Ray crystallographic analysis was performed on the compound to which had been assigned the structure 1,2,3,5-tetra-O-acetyl-4-deoxy-4-C-[(S)-ethylphosphinyl]-α-d-ribofuranose. The results showed that the compound has the proposed configuration, the five-membered ring is in the ³T₂ conformation with a tendency towards the E₂ form, the substituents on C-1, C-4, and P-5 are linked bisectionally, and the acetoxyl groups on C-2 and C-3 are respectively attached axially and equatorially. Based on the X-ray crystallographic and ¹H-n.m.r.-spectral data, favored conformations of P-in-ring analogs of aldopentofuranose peracetates in solution are discussed.     

A 13c-n.m.r. study of 1,6:2,3- and 1,6:3,4-dianhydro-β-D-hexo-pyranoses and their O-acetyl and deoxy derivatives

¹³C-N.m.r. spectra of all possible 1,6:2,3- and 1,6:3,4-dianhydro-β-D-hexo-pyranoses and their O-acetyl and deoxy derivatives are presented. Relations between chemical shifts of certain carbon atoms and the structure of the dianhydrides are outlined, and their application in structural analysis is discussed. Inversion of configuration of the oxirane ring from the endo to the exo position is associated with typical upfield-shifts for oxirane-ring carbon atoms C-2 or C-4, respectively. Possible inter-relationships between ¹³C-chemical shifts and steric and polar interactions in the dianhydro derivatives are discussed.     

Dual Role of Methionine in the Biosynthesis of Diacylglyceryltrimethylhomoserine in Chlamydomonas reinhardtii

Biosynthesis of the polar group of diacylglyceryl-O-4′-(N,N,N-trimethyl)homoserine (DGTS) was studied in intact cells of Chlamydomonas reinhardtii Dangeard. Among the three C₄ amino acids tested, only l-methionine could specifically inhibit the photosynthetic incorporation of [¹⁴C]NaHCO₃ into the polar group of DGTS. The radioactivity in l-[¹⁴C]methionine, which was labeled at either the C3 + C4, the C1, or the methyl carbon, was efficiently incorporated into the polar group of DGTS. These results suggest that the C₄ backbone and the S-methyl group of l-methionine are precursors to the C₄ backbone and the N-methyl groups of DGTS, respectively.