Inter-residue Hydrogen Bonds Research Articles

Molecular dynamics simulations of maltose in water

The conformational preferences and flexibility of α-maltose were calculated using a modified GROMOS potential energy function. Six molecular dynamics (MD) simulations of α-maltose with explicit inclusion of water were run for up to 1000 ps each, starting from different conformations of the glycosidic linkage, the hydroxymethyl groups, and the hydroxyl groups. Comparison of calculated ensemble-averaged optical rotations with experimental data demonstrated an excellent agreement. Reasonable agreement was also found between experimental and calculated time-averaged NMR parameters. The global minimum centered at ϕ/ ψ 3 = −49°/−36° was populated to more than 90% of the time. The second minimum with ≈ 11 kJ/mol higher potential energy at ϕ/ ψ = − 29°/ − 173° represented the inverted conformation. Transitions between both minimum regions were only found from the local into the global minimum within the total simulation time of 5400 ps. The overall ratio between the staggered populations of the hydroxymethyl groups is gg: gt: tg = 70:23:6 for the reducing glucose, and gg: gt: tg = 55:38:6 for the nonreducing residue. Average lifetimes of the rotamers of the hydroxymethyl groups range between 5 ps for tg and 700 ps for gg conformers. The lowest energy barriers between the rotameric populations were estimated to be between 12 kJ/mol and 16 kJ/mol. Cluster analysis techniques employed to analyze the large amount of data in multidimensional space revealed correlations between the glycosidic linkage and the staggered forms of the hydroxymethyl groups. Interresidue hydrogen bonds that were found in less than 5% of all conformations occurred when the glycosidic linkage adopted conformations with relatively high ϕ and ψ values. Several additional minima that had been found from in vacuo studies are not stable once water is included since the importance of intramolecular hydrogen bonds is drastically reduced. Methodological aspects and the efficiency of MD simulations for reaching conformational equilibria are discussed.

Interresidue hydrogen bonding in a peptide nucleic acid.RNA heteroduplex.

Previous molecular mechanics calculations suggest that strands of peptide nucleic acids (PNAs) and complementary oligonucleotides form antiparallel duplexes stabilized by interresidue hydrogen bonds. In the computed structures, the amide carbonyl oxygen nearest the nucleobase (O7') forms an interresidue hydrogen bond with the backbone amide proton of the following residue, (n + 1)H1'. Of the 10 published two dimensional 1H NMR structures of a hexameric PNA.RNA heteroduplex. PNA(GAACTC).r(GAGUUC), 9 exhibit two to five potential interresidue hydrogen bonds. In our minimized average structure, created from the coordinates of these 10 NMR structures, three of the five possible interresidue hydrogen bond sites within the PNA backbone display the carbonyl oxygen (O7') and the amide proton (n + 1)H1' distances and N1'-H1'-(n - 1)O7' angles optimal for hydrogen bond formation. The finding of these interresidue hydrogen bonds supports the results of our previous molecular mechanics calculations.

Molecular modeling of saccharides, 7. The conformation of sucrose in water: A molecular dynamics approach

AbstractA molecular mechanics analysis of the conformational properties of sucrose in vacuo in terms of the intersaccharidic torsion angles Φ and Ψ, revealed three energy minima. The geometry of the global minimum‐energy closely resembles the solid‐state structure. Most notably, the interresidue hydrogen bonding interaction 2g‐O…︁HO‐1f present in the crystal, is retained under vacuum boundary conditions, indicating the molecular geometries adopted in the crystal lattice and in vacuo to be similar. For aqueous solutions, detailed molecular dynamics simulations of sucrose „soaked”︁ with 571 water molecules in a periodic box (truncated octahedron), revealed this direct H‐bond interaction to be replaced by an indirect, water‐mentioned one: an interresidue water‐bridge of the 2g‐O…︁H2O…︁HO‐1f type prevailed with a high significance and a long life‐time. This means the linkage geometry of sucrose in water–despite the absence of direct interresidue hydrogen bonds–again closely resembles the solid‐state and in vacuo geometry in terms of the orientation of the glucose and the fructose unit relative to one another. The solution dynamics of, and the hydration around sucrose were analyzed in terms of pair distribution functions. These indicate strong hydrogen bonding between all sucrose hydroxyls (as donors and acceptors) and water within a first, well‐defined hydration layer (hydroxyl‐oxygen–water distances 1.8–3.5 Å), whereas the acetalic oxygens are engaged to a lesser extent as H‐bond acceptors. The second hydration shell (>4 Å) is rather diffuse and less pronounced, indicating those water molecules to be in a disordered state. The implications of the hydration shell and the water bridge on the crystallization process of sucrose and on binding towards transporter proteins, and the sweet‐taste receptor, are discussed. Other sucrose conformations that may conceivably exist in aqueous solution, may have eluded the MD simulation search. The umbrella sampling technique was applied for establishing the free energy profile as a function of the intersaccharidic torsion angles. The resulting concise picture of the dynamics of sucrose in aqueous solution, encompassing the entire conformational space available, revealed only two energy minima. Of these, the by far, most populated global minimum structure corresponded to the most stable solution geometry, as found by molecular dynamics.

NMR, Molecular Modeling, and Crystallographic Studies of Lentil Lectin-Sucrose Interaction

The conformational features of sucrose in the combining site of lentil lectin have been characterized through elucidation of a crystalline complex at 1.9-A resolution, transferred nuclear Overhauser effect experiments performed at 600 Mhz, and molecular modeling. In the crystal, the lentil lectin dimer binds one sucrose molecule per monomer. The locations of 229 water molecules have been identified. NMR experiments have provided 11 transferred NOEs. In parallel, the docking study and conformational analysis of sucrose in the combining site of lentil lectin indicate that three different conformations can be accommodated. Of these, the orientation with lowest energy is identical with the one observed in the crystalline complex and provides good agreement with the observed transferred NOEs. These structural investigations indicate that the bound sucrose has a unique conformation for the glycosidic linkage, close to the one observed in crystalline sucrose, whereas the fructofuranose ring remains relatively flexible and does not exhibit any strong interaction with the protein. Major differences in the hydrogen bonding network of sucrose are found. None of the two inter-residue hydrogen bonds in crystalline sucrose are conserved in the complex with the lectin. Instead, a water molecule bridges hydroxyl groups O2-g and O3-f of sucrose.

Evidence for a Transient Interresidue Hydrogen Bond in Sucrose in Aqueous Solution Obtained by Rotating-Frame Exchange NMR Spectroscopy Under Supercooled Conditions

We have used the hydroxyl protons of sucrose dissolved in supercooled water as NMR probes for the detection of intramolecular hydrogen bonds. Neither the measured OH temperature shift coefficients, 3 J HCOH scalar couplings, isotope-induced 13C chemical shifts (Δδ COH/COD) nor OH exchange rates allowed us to single out any hydroxyl group in sucrose with characteristics indicative of involvement in strong hydrogen bonding. However, two-dimensional rotating-frame exchange (ROESY) spectroscopy revealed a direct exchange between the glucosyl OH2 and fructosyl OH1 protons. We conclude that an O2g::H::O1f interresidue hydrogen bond transiently exists in sucrose in aqueous solution. ROESY of sugars in supercooled water is proposed as a novel method to detect this type of weak hydrogen bonding.

Chain Conformation of a Glucurono-xylo-mannan Isolated from Fruit Body of Tremella fuciformis Berk

Abstract A possible chain conformation of the acidic heteropolysaccharide isolated from the fruit body of Tremella fuciformis Berk (Shirokikurage) was proposed by the X-ray diffraction study combined with the computational model building technique. The polysaccharide consists of a linear backbone of 1,3-linked α-D-mannose which is highly substituted with β-D-xylose, β-D-glucuronic acid, and 1,2-linked β-D-xylobiose units at the C2 position of the mannose residue. It was suggested from the X-ray data, together with the knowledge of the chain conformations proposed for other 1,3-linked α-D-glycans, that the backbone conformation has the left-handed, three-fold helical symmetry. Orientations of the side group residues on the mannan backbone were suggested from the theoretical calculations. The proposed conformation of a repeating unit of the helical model consisted of six mannose residues and three side group residues in the 2.42 nm distance along the fiber axis. Two interresidue hydrogen bonds were observed...

Structural fluctuation of methyl N,N′-diacetyl-β- d-chitobioside in vacuo and in aqueous solution: Molecular dynamics simulations and proton NMR spectroscopy

Molecular dynamics (MD) simulations of methyl N,N′-diacetyl-β- d-chitobioside (GIcNAcβ-(1 → 4)GIcNAcβ-OMe) have been performed both in vacuo and in aqueous solution with the explicit inclusion of the solvent water molecules. The β-(1 → 4) glycosidic linkage fluctuates considerably, over a range of ± 10°, in each of the MD simulations in vacuo and in aqueous solution. The intra- and inter-residue hydrogen bonds in vacuo are replaced by intermolecular hydrogen bonds with the solvent water molecules in aqueous solution. Multiple conformations ( gg and gt) exist for the exocyclic hydroxymethyl groups. The results of the MD simulations are compared with those of 1H- 1H nuclear Overhauser effect measurements.

Peptide nucleic acid (PNA) conformation and polymorphism in PNA-DNA and PNA-RNA hybrids.

Two hydrogen-bonding motifs have been proposed to account for the extraordinary stability of polyamide "peptide" nucleic acid (PNA) hybrids with nucleic acids. These interresidue- and intraresidue-hydrogen-bond motifs were investigated by molecular mechanics calculations. Energy-minimized structures of Watson-Crick base-paired decameric duplexes of PNA with A-, B-, and Z-DNA and A-RNA polymorphs indicate that the inherent stability of the complementary PNA helical structures is derived from interresidue, rather than from intraresidue, hydrogen bonds in all hybrids studied. Intraresidue-hydrogen-bond lengths are consistently longer than interresidue hydrogen bonds. Helical strand stability with interresidue hydrogen bond stabilization follows the order: B-(DNA.PNA) > A-(DNA.PNA) congruent to A-RNA.PNA > Z-(DNA.PNA). In the triplex hybrids A-(RNA.PNA2) and B-(DNA.PNA2), differences between stabilities of the two decamers of thyminyl PNA with lysine amide attached to the C terminus (pnaT)10 strands are small. The Hoogsteen (pnaT)10 strands are of slightly higher potential energy than are the Watson-Crick (pnaT)10 strands. Antiparallel arrangement of PNAs in the triplex is slightly favored over the parallel arrangement based on the calculations. Examination by molecular mechanics of the PNA.DNA analogue of the NMR-derived structure for the B-double-stranded DNA dodecamer d(CG-CAAATTTGCG)2 in solution suggests that use of all bases of the genetic alphabet should be possible without loss of the specific interresidue-hydrogen-bonding pattern within the PNA strand.

Molecular mechanics calculations of the structures of polyamide nucleic acid DNA duplexes and triple helical hybrids.

Polyamide nucleic acids (PNAs) have emerged as useful agents for recognition of single- and double-stranded nucleic acids. Interresidue hydrogen bonds between the amide carbonyl nearest the nucleobase and chain NH moieties provide inherent stability to the helical conformation of PNA 1. Moving the amide carbonyl away from the nucleobase to the backbone, and replacing it with a methylene group, results in 2 lacking the stabilizing hydrogen bond. Oligomers of 2 do not interact with DNA. Modeling suggests that 2 displays a more extended conformation than 1, and nucleobase orientation is disrupted in 2 in the absence of a complementary DNA strand. This is in contrast to 1, which retains a centrosymmetric arrangement of nucleobases. Structures for 1-T10.DNA and (1-T10)2.DNA species spanned by a pyrimidine strand (D-loop) were constructed. In the triple helical (1-T10)2.DNA structure, the two PNA strands form the complementary Watson-Crick paired strand and the Hoogsteen base-paired strand in the major groove of the 1.DNA duplex. The PNA strands are proposed to bind antiparallel to one another in (1-T10)2.DNA structure. The factors suggested to account for the stability of this 2:1 complex are (i) a hydrophobic attraction between two PNA backbones and (ii) a favorable electrostatic effect resulting from replacement of a phosphodiester backbone by a neutral peptide backbone.

1H- and 13C-NMR studies of solutions of hyaluronic acid esters and salts in methyl sulfoxide: comparison of hydrogen-bond patterns and conformational behaviour

The 1H- and 13C-NMR spectra of the ethyl and benzyl esters and the tetrabutylammonium and tetraethylammonium salts of hyaluronic acid { ▪ 2)-β- d-Glc pA-(1 → 3)-β- d-Glc pNAc-(1 ▪ n } in Me 2SO- d 6 have been assigned using 1D and 2D techniques. The chemical shifts of the resonance of GlcNAc C-3 suggest that the relative orientations of the monosaccharides at the (1 → 3) linkage in the esters and salts are different. Small differences in the chemical shifts of the resonance GlcA C-4 suggest only a slight conformational variation around the (1 → 4) linkage. The 13C-NMR data also suggest similarities in conformation between the esters in Me 2SO- d 6 and the salts in water. The chemical shifts of the 1H resonances for NH and OH groups and their temperature dependence for the esters and salts in Me 2SO reveal markedly stronger inter-residue hydrogen bonds between the carboxyl and NH groups and between HO-4 of GlcA and O-5 of GlcNAc for the salts. The 3 J 2,NH values indicate a slightly different orientation for the acetamido group. For solutions in Me 2SO, the higher segmental flexibility of the esters is supported by the line widths, whereas the reduced viscosity for the tetrabutylammonium salt showed a sigmoidal concentration dependence and suggests association of chains which could contribute to the segmental rigidity. The linear concentration dependence for the benzyl ester suggests a higher overall flexibility without chain association.

Crystal structure and n.m.r. analysis of lactulose trihydrate

The 13C CPMAS n.m.r. spectrum of 4-O-β-d-galactopyranosyl-d-fructose (lactulose) trihydrate, C12H22O11·3 H2O, identifies the isomer in the crystals as the β-furanose. This is confirmed by a crystal structure analysis, using CuKα X-ray data at room temperature. The space group is P212121, with Z = 4 and cell dimensions a = 9.6251(3), b = 12.8096(3), c = 17.7563(4) Å. The structure was refined to R = 0.031 and Rw 0.025 for 1929 observed structure amplitudes. All the hydrogen atoms were unambigously located on difference syntheses. The conformation of the pyranose ring is the normal 4C1 chair and that of the furanose ring is 4T3. The 1 → 4 linkage torsion angles are O-5′−C-1′−O-1′−C-4 = −79.9(2)° and C-1′−O-1′−C-4−C-5 = − 170.3(2)°. All hydroxyls, ring and glycosidic oxygens, and water molecules are involved in the hydrogen bonding, which consists of infinite chains linked together by water molecules to forma three-dimensional network. There is a three-centered intramolecular, interresidue hydrogen bond from O-3-H to O-5′ and O-6′. The n.m.r. spectrum of the amorphous, dehydrated trihydrate suggests the occurrence of a solid-state reaction forming the same isomeric mixture as was observed in crystalline anhydrous lactulose, although the mutarotation of the trihydrate when dissolved in Me2SO is very low.

1H-NMR study of GM2 ganglioside: evidence that an interresidue amide-carboxyl hydrogen bond contributes to stabilization of a preferred conformation

Several properties of the exchangeable amide protons of the ganglioside GM2 were studied in detail by 1H-NMR spectroscopy in fully deuterated dimethylsulfoxide [2H6]DMSO/2% H2O, and compared with data obtained for the simpler constituent glycosphingolipids GA2 and GM3. In addition to chemical shifts, 3J2,HN coupling constants, and temperature shift coefficients, the kinetics of NH/2H chemical exchange were examined by following the disappearance of the amide resonances in [2H6]DMSO/2% 2H2O. The results included observation of an increase in half-life of the N-acetylgalactosamine acetamido HN by more than an order of magnitude in GM2 compared to GA2, attributable to the presence of the additional N-acetylneuraminic acid residue. Additional one-dimensional dipolar cross relaxation experiments were also performed on nonexchangeable protons of GM2. The results of all of these experiments support a three-dimensional model for the terminal trisaccharide in which a hydrogen bond is formed between the N-acetylgalactosamine acetamido NH and the N-acetylneuraminic acid carboxyl group. The interaction is proposed to be of the pi-acceptor type, a possibility which has not yet been explored in the literature on carbohydrates. The proposed model is discussed in comparison with that of Sabesan et al. (1984, Can J Chem 62:1034-45), and the models of GM1 proposed more recently by Acquotti et al. (1990, J Am Chem Soc 112:7772-8) and Scarsdale et al. (1990, Biochemistry 29:9843-55).

A comparative NMR study between the macrolide antibiotic roxithromycin and erythromycin A with different biological properties

1H nuclear Overhauser enhancement studies and 1H NMR 3J analysis establish the similarity between the major solution-state conformation of roxithromycin (1) and the erythromycin (2). A major difference between the structure of antibiotics 1 and 2 is the replacement of the 9-keto group in 2 by a 9-[O-(2,5-dioxahexyl)oxime] group. The NOE studies show that this oxime chain is oriented above the macrocyclic lactone ring and that the oxygen atoms of this chain are engaged in tight hydrogen bonding with a water molecule and with the 6- and 11-hydroxyl groups of the macrocycle. It results in a globular form of the whole roxithromycin molecule. These data explain also a relative hydrophobicity of this antibiotic. Erythromycin A (2), which presents a less rigid macrocycle with two free hydroxyl groups (6-OH and 11-OH), forms a dimer detected by FAB mass spectroscopy. 1H and 13C NMR relaxation measurements (T1) for both antibiotics show that interresidue hydrogen bonds in roxithromycin reduce the rotational freedom of the macrocyclic lactone ring and consequently the motions of desosamine and cladinose sugars. In another way, an ionization of the amino function occurs in the various media according to the nature of the antibiotic. This would allow the reactivity modification of the desosamine unit. In the biological study, the modifications of the 455-nm metabolite-cytochrome P-450 complex formation are observed.

Solution conformation of the branch points of N-linked glycans: synthetic model compounds for tri'-antennary and tetraantennary glycans.

The solution conformation of model compounds for the tri'-antennary and tetraantennary (six-arm) branch point of N-linked glycans has been determined through the use of chemical shift, relaxation, and nuclear Overhauser enhancement data. The object was to establish the conformation about the glycosidic linkages in the N-linked substructure GlcNAc(beta 1,6) [GlcNAc(beta 1,2)] Man(alpha)- by estimation of values for the appropriate glycosidic torsional angles. The GlcNAc(beta 1,6) linkage in a trisaccharide model compound was found to be constrained to a narrow rotameric subpopulation about the substituted Man C5-C6 bond (omega = -60 degrees) and a narrow range of possible phi - psi values. Free rotation about the Man C5-C6 bond was obstructed by unfavorable steric interactions between the GlcNAc(beta 1,6) and GlcNAc(beta 1,2) residues. A phi, psi value of 55 degrees, 190 degrees was found to be consistent with the NMR data for the GlcNAc(beta 1,6) linkage. However, the value of psi appears to be "virtual" in that the molecule is in equilibrium between two different values (90 degrees and 252 degrees). For the GlcNAc(beta 1,2) linkage, complete agreement between all the observed NMR parameters and all the calculated ensemble average values could only be obtained with a set of potential energy functions which included hydrogen bonding. Other choices of potentials yielded calculated values that disagreed with at least two of the observed quantities. As a result, we infer that an interresidue hydrogen bond is formed, and we find it to be between the GlcNAc(beta 1,2) ring oxygen and the Man C3 hydroxyl.(ABSTRACT TRUNCATED AT 250 WORDS)

Co-operative and competitive hydrogen bonding in sucrose determined by SIMPLE 1H n.m.r. spectroscopy

SIMPLE1H n.m.r. measurements of isotope-shifted resonance for hydroxy groups in sucrose show that hydrogen bonding in solution is different from that observed in the solid state viz. there are two inter-residue hydrogen bonds in competition for one acceptor group (i.e. OH1′⋯ O2 vs.OH3′⋯ O2) and an intramolecular hydrogen-bond network that is nucleated by the inter-residue hydrogen bonds.

An empirical potential for the O-H ⋯ O hydrogen bond: Part 2. Comparison with observed hydrogen bond geometries

The room temperature distribution of O-H ⋯ O hydrogen bond geometries has been predicted by a Monte Carlo calculation, with an empirical potential energy function for the hydrogen bond. The results are compared with a recent survey of hydrogen bonds in carbohydrate crystal structures. The calculated and observed distributions of the O-H ⋯ O angle have mean values of 165.5° and 167.1° respectively. Both the theoretical and experimental results suggest that short O ⋯ H hydrogen bonds tend to be more linear than long O ⋯ H bonds. The distribution of hydrogen bonding within the lone pair plane of the acceptor oxygen atom is predicted to be broader than the distribution perpendicular to this plane, in agreement with the experimental data. The empirical hydrogen bond function, in conjunction with the molecular mechanics program MMI, has also been used to predict the geometries of inter-residue hydrogen bonds in five disaccharides. The O ⋯ H distances and O-H ⋯ O angles are reproduced with r.m.s. deviations of 0.06 Å and 9° respectively.

Molecular structures for microbial polysaccharides. X-ray diffraction from the capsular polysaccharide of Klebsiella K-type 5

Fibre Type X-ray diffraction patterns have been obtained from oriented, semicrystalline films prepared from the sodium salt form of the capsular polysaccharide of K5. The molecule has a linear trisaccharide repeating sequence containing a 1,3 linked β- d-glucuronic acid and a 1,4 linked β- d-glucose residue, resulting in a backbone linkage geometry of Man(1 eq-4e1)-GIcUA (1-eg-4eg) Gle (1 eq-3 eq) Man. It also contains an O-acetyl group and two charged groups, namely a uronic acid and a pyruvate. Analysis of the diffraction results gives rise to an extended two-fold helical conformation with an axially projected advance of 1.35 nm which correlates directly with the covalent repeating sequence. X-ray diffraction patterns from preparations of deacetylated K5 polysaccharide showed similar conformations for the individual helices but the interchain packing arrangements are different. In each case, isolated helices have been computer generated using molecular model building procedures and the most favourable conformations for both preparations were those which contained three stabilizing interresidue hydrogen bonds, one across each of the glycosidic linkages.

Conformational analysis of cellobiose, cellulose, and xylan

All of the likely conformations of cellobiose, cellulose, and xylan have been explored systematically by using an electronic computer, assuming the ring conformations and (C-1)-O-(C-4′) angle for each pair of residues to be fixed and derivable from known crystal structures. The absolute van der Waals energies, but not the relative energies of different conformations, are sensitive to the choice of energy functions and atomic coordinates. The conformation of cellobiose in the crystal occurs near the minimum for intramolecular van der Waals interactions, perhaps slightly displaced to allow formation of an inter-residue hydrogen bond. The Hermans chain conformation for cellulose corresponds to a somewhat higher van der Waals energy, but this is probably offset by efficient crystal packing resulting from the two fold screw axis, and the hydrogen bond remains. The Meyer and Misch conformation is unlikely, because of its high van der Waals energy and for other reasons. The results lead to possible explanations of the known conformational stiffness of cellulose and its solubility properties in alkali. The characteristics of xylan conformations have been compared with cellulose.