Inter-residue Hydrogen Bonds Research Articles

Flexibility in the Inducer Binding Region Is Crucial for Allostery in the Escherichia coli Lactose Repressor

Lactose repressor protein (LacI) utilizes an allosteric mechanism to regulate transcription in Escherichia coli, and the transition between inducer- and operator-bound states has been simulated by targeted molecular dynamics (TMD). The side chains of amino acids 149 and 193 interact and were predicted by TMD simulation to play a critical role in the early stages of the LacI conformational change. D149 contacts IPTG directly, and variations at this site provide the opportunity to dissect its role in inducer binding and signal transduction. Single mutants at D149 or S193 exhibit a minimal change in operator binding, and alterations in inducer binding parallel changes in operator release, indicating normal allosteric response. The observation that the double mutant D149A/S193A exhibits wild-type properties excludes the requirement for inter-residue hydrogen bond formation in the allosteric response. The double mutant D149C/S193C purified from cell extracts shows decreased sensitivity to inducer binding while retaining wild-type binding affinities and kinetic constants for both operator and inducer. By manipulating cysteine oxidation, we show that the more reduced state of D149C/S193C responds to inducer more like the wild-type protein, whereas the more oxidized state displays diminished inducer sensitivity. These features of D149C/S193C indicate that the novel disulfide bond formed in this mutant impedes the allosteric transition, consistent with the role of this region predicted by TMD simulation. Together, these results establish the requirement for flexibility in the spatial relationship between D149 and S193 rather than a specific D149-S193 interaction in the LacI allosteric response to inducer.

Methyl 3-O-α-D-mannopyranosyl β-D-glucopyranoside tetrahydrate

The title compound, C13H24O11·4H2O, forms extended hydrogen-bonded networks. These are present between disaccharides, but not as inter-residue hydrogen bonds, as well as to water mol­ecules that in addition form an inter­molecular chain of hydrogen bonds. The conformation of the disaccharide is described by the glycosidic torsion angles ϕH = −34° and ψH = −5°. Macroscopically, the disaccharide was observed to be hygroscopic.

Effects of the minor groove pyrimidine nucleobase functional groups on the stability of duplex DNA: The impact of uncompensated minor groove amino groups

DNA sequences containing four types of analog nucleosides are described. All four are pyridine derivatives constructed as C-nucleosides so that they mimic the pyrimidine derivatives 2'-deoxyuridine, thymidine or 2'-deoxycytidine, but in all cases the analogs lack the corresponding O2-carbonyls that in duplex DNA are located in the minor groove. In place of the O2-carbonyl is a hydrogen atom, a polar fluorine atom, or a nonpolar methyl group. The described C-nucleosides have native-like bidentate Watson-Crick hydrogen-bonding faces and can form essentially normal W-C base pairs of varying stability with A or G. In each modified base pair, two inter-residue hydrogen bonds should be present. In spite of a common number of interstrand hydrogen bonds, the thermodynamic stabilities of the prepared duplexes, each containing two analog base pairs, vary dramatically. Most notably, base pairs containing uncompensated purine amino groups (those lacking a hydrogen-bonding partner) in the minor groove exhibit the most dramatic reductions in thermodynamic stability. Removal of such uncompensated amino groups results in increased duplex stability. Base pairs containing fluorine in the minor groove positioned adjacent to an amino group seem to enhance duplex stability marginally (relative to --H or --CH(3)), but there is little evidence to suggest that fluorine is an effective hydrogen-bonding partner in these systems. The presence of minor groove methyl groups results in the least stable duplexes in each series of sequences.

Methyl 4‐O‐β‐L‐Galactopyranosyl‐β‐D‐glucopyranoside (Methyl β‐L‐Lactoside).

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Methyl 4-O-β-L-galactopyranosyl-β-D-glucopyranoside (methyl β-L-lactoside)

Methyl beta-L-lactoside, C13H24O11, (II), is described by glycosidic torsion angles phi (O5Gal-C1Gal-O4Glc-C4Glc) and psi (C1Gal-O1Gal-C4Glc-C5Glc) of 93.89 (13) and -127.43 (13) degrees , respectively, where the ring atom numbering conforms to the convention in which C1 is the anomeric C atom and C6 is the exocyclic hydroxymethyl (CH2OH) C atom in both residues (Gal is galactose and Glc is glucose). Substitution of L-Gal for D-Gal in the biologically relevant disaccharide, methyl beta-lactoside [Stenutz, Shang & Serianni (1999). Acta Cryst. C55, 1719-1721], (I), significantly alters the glycosidic linkage interface. In the crystal structure of (I), one inter-residue (intramolecular) hydrogen bond is observed between atoms H3OGlc and O5Gal. In contrast, in the crystal structure of (II), inter-residue hydrogen bonds are observed between atoms H6OGlc and O5Gal, H6OGlc and O6Gal, and H3OGlc and O2Gal, with H6OGlc serving as a donor with two intramolecular acceptors.

Protein Misfolding and Amyloid Formation for the Peptide GNNQQNY from Yeast Prion Protein Sup35: Simulation by Reaction Path Annealing

We study the early steps of amyloid formation of the seven residue peptide GNNQQNY from yeast prion-like protein Sup35 by simulating the random coil to beta-sheet and alpha-helix to beta-sheet transition both in the absence and presence of a cross-beta amyloid nucleus. The simulation method at atomic resolution employs a new implementation of a Langevin dynamics "reaction path annealing" algorithm. The results indicate that the presence of amyloid-like cross-beta-sheet strands both facilitates the transition into the cross-beta conformation and substantially lowers the free energy barrier for this transition. This model systems allows us to investigate the energetic and kinetic details of this transition, which is consistent with an auto-catalyzed, nucleation-like mechanism for the formation of beta-amyloid. In particular, we find that electrostatic interactions of peptide backbone dipoles contribute significantly to the stability of the beta-amyloid state. Furthermore, we find water exclusion and interactions of polar side-chains to be driving forces of amyloid formation: the cross-beta conformation is stabilized by burial of polar side-chains and inter-residue hydrogen bonds in the presence of an amyloid-like "seed". These findings are in support of a "dry, polar zipper model" of amyloid formation.

Helix-Forming Carbohydrate Amino Acids

[reaction: see text] The solution-phase conformational properties of tetrameric and octameric chains of C-glycosyl alpha-d-lyxofuranose configured tetrahydrofuran amino acids (where the C-2 and C-5 substituents on the tetrahydrofuran ring are trans to each other) were examined using NMR and IR and CD in organic solvents. Studies by NMR and IR demonstrated that in chloroform solution, the tetramer 7 does not adopt a hydrogen-bonded conformation whereas the octamer 10 populates a well-defined helical secondary structure stabilized by 16-membered (i, i - 3) interresidue hydrogen bonds, similar to a pi-helix. Circular dichroism studies in trifluoroethanol are consistent with this conformation for the octamer 10, and also indicate that the tetramer 7 adopts a rigid conformation not stabilized by hydrogen bonds.

Fluorinated cellobiose and maltose as stand-ins for energy surface calculations

To better understand computational predictions of disaccharide conformations, ϕ, ψ maps were constructed for two analogs in which all hydroxyl groups were replaced with fluorine atoms (F-cellobiose and F-maltose). These molecules do not permit hydrogen bonding but should give better steric representation than analogs in which hydrogen atoms replaced exo-cyclic groups. Hartree Fock and B3LYP density functional quantum mechanics (QM) theory were used. The preferred ring shape for fluorinated glucose depends on the level of QM theory, but over the limited ϕ, ψ space that was studied, the rings remained in the 4 C 1 form. Also, fluorine atoms are remote enough that they do not affect the torsional energies for the glycosidic bonds. F-Cellobiose maps were predictive of the conformations in crystals, but F-maltose maps were less so. The QM F-cellobiose map and an MM4::QM hybrid map for cellobiose itself were similar. However, the hybrid maltose map had many more experimental conformations within its 2-kcal/mol contour than did the QM F-maltose map. The apparent mean strength of an intra-molecular, inter-residue hydrogen bond is about 3 kcal/mol, based on the energy for many of the hydrogen bonded maltose structures on the F-maltose map. The F-maltose map was similar to a new QM map for an analog of maltose in which all hydroxyl groups were replaced with hydrogen atoms.

Explicit-Solvent Molecular Dynamics Simulations of the β(1→3)- and β(1→6)-Linked Disaccharides β-Laminarabiose and β-Gentiobiose in Water

The conformational preferences about the glycosidic linkages present in β-laminarabiose and β-gentiobiose in water are investigated by comparing molecular dynamics (MD) simulations with results from NMR spectroscopy (coupling constants, NOE-derived distances), X-ray crystallography (structures), and molecular mechanics (adiabatic energy maps). The simulations are performed using the OPLS−AA−SEI force field recently developed for hexopyranoses and extended to account for the properties of the linkages present in the two disaccharides. The experimental and theoretical results for β-laminarabiose are very consistent and reveal a clear correlation between the conformation around the dihedral angle ψ and the presence of an interresidue hydrogen bond (from the 4-hydroxyl group of the reducing residue to the ring oxygen of the nonreducing residue). The solvent (water) plays an essential role in determining the preferential orientation about ψ, by dramatically reducing the strength of this intramolecular hydrogen bond. Application of the OPLS−AA−SEI force field to β-gentiobiose requires significant adjustments of the torsional parameters and electrostatic scaling scheme. After optimization of the force field based on ab initio calculations in a vacuum and on the experimental population profile around the dihedral angle ω in water, the OPLS−AA−SEI force field is able to give a realistic representation of the conformational behavior of the β(1→6) linkage on the nanosecond time scale. As expected, the glycosidic dihedral angles in this linkage present an enhanced flexibility compared to the β(1→3) linkage. The results of the two simulations point (in line with previous studies) toward the need of developing a new Karplus-type equation relating hetero-nuclear 3JC,H coupling constants to the glycosidic dihedral angle φ. They also suggest that the Karplus-type equation of Stenutz et al. for the homo-nuclear 3JH,H coupling constant is superior to the widely used equation of Haasnoot et al.

Conformational Analysis of C‐Trehaloses Using Molecular Mechanics Calculations

Relaxed‐residue energy maps based on the MM3 force field were computed for the three C‐linked (1‐1) d‐glucosyl disaccharides, C‐trehaloses: the axial–axial linked α,α‐trehalose, the axial–equatorial α,β‐trehalose and the equatorial–equatorial linked β,β‐trehalose. Optimized structures were calculated on a 20°‐grid spacing of the torsional angles about the C‐glycosidic bonds. Boltzman weighted 3J coupling constants were calculated and compared to the experimental values; they are satisfactory. The general shape of the energy maps indicates that α,α‐trehalose is a quite rigid molecule adopting only one conformation around the C‐glycosidic linkage, whereas the other two isomers are rather flexible. Compared to the corresponding O‐disaccharides α,β‐ and β,β‐trehaloses exhibit a larger number of low energy conformers and a larger area of the map energy < 8 kcal/mol. The preferred conformations of the axial C‐glycosidic bond are in agreement with the exo‐anomeric effect. Equatorial C‐ glycosidic bonds are rather flexible, influenced by the polarity of the milieu and the formation of interresidue hydrogen bonds. #Associated with the Université Faurier, Grenoble, France.

Bend ribbon-forming tetrahydrofuran amino acids.

Short oligomeric chains of C-glycosyl beta-D-arabinofuranose configured tetrahydrofuran amino acids (where the C-2 and C-5 substituents of the tetrahydrofuran ring are cis to each other) exhibit a well-defined repeating turn secondary structure stabilised by (i, i - 2) inter-residue hydrogen bonds. This is in contrast to the epimeric alpha-D-arabinofuranose oligomer (where the C-2 and C-5 substituents of the tetrahydrofuran ring are trans to each other) in which there is no indication of any secondary structure in solution.

Conformational Dynamics of Hyaluronan in Solution. 2. Mode-Coupling Diffusion Approach to Oligomers

A detailed study of structure and dynamics of hyaluronan oligomers (UA)4 and (UA)2 is presented. Recent advances in macromolecule diffusion theory are applied to second order in the mode-coupling expansion to derive second-rank time-correlation functions of the C−H vectors along the chains. The required equilibrium averages are approximated by time averages along an atomistic molecular dynamics simulation. The results are compared with experimental 13C NMR relaxation parameters of different nuclei in the molecule. The pronounced structure in the relaxation pattern found in the experiments for (UA)4 can be qualitatively interpreted in terms of rotational diffusion anisotropy with partially screened hydrodynamic interactions. Interresidue hydrogen bonds concerning the side chains are weak and do not have significant local effects while O5(i)−HO3/4(i + 1) hydrogen bonds can play a significant role in coupling conformational degrees of freedom with solvation. The implications of this study on the knowledge of...

Microscopic study of chiral interactions in langmuir monolayer: monolayers of N-palmitoyl aspartic acid and N-stearoyl serine methyl ester

In the present paper, we theoretically investigate the effect of chiral interaction on the morphology of the domain in the condensed phase of amino acid amphiphiles like N-palmitoyl aspartic acid and N-stearoyl serine methyl ester. We derived relations to calculate the intermolecular potential of a pair of chiral molecules, which is dependent on the intermolecular separation and the mutual orientation of the molecules. The calculation is carried out based on an effective pair potential description of the groups attached to the chiral center. It is observed that the intermolecular interaction is most favorable at a twist between the azimuthal orientations of the same type of enantiomeric molecules and the energy difference between the twisted arrangement and the parallel arrangement (of neighboring molecules) is of the same order as the intermolecular hydrogen bond energy of the corresponding amino acid head groups. Thus, the observed curvature of the domain shape of amino acid amphiphiles is suggested to be due to the twist at the condensed phase/fluid interface where the interresidue (amino acid) hydrogen bond cycle is not as regular as within the condensed phase. Secondly, we also calculated the interaction energy of an external molecule with all molecules within a circular domain, having the same azimuthal orientation. It is observed that the interaction energy is rather anisotropic for enantiomers in the compressed state (smaller intermolecular separation). The interaction energy has a symmetric profile around the domain composed of a pair of mirror image isomers. Thus, the excess free energy at the condensed phase/fluid interface could be anisotropic for domains where the molecules have parallel arrangement throughout the lattice and this effect may act in concert with the intrinsic tendency to have an intermolecular twist due to chirality. The possibility of the relationship between the molecular twist and the handedness of the curvature of the domain is also discussed.

Absence of secondary structure in a carbopeptoid tetramer of a trans-5-aminomethyl-tetrahydrofuran-2-carboxylate

Whereas trimers and tetramers of β- C- d-arabinofuranosyl carbohydrate amino acids adopt well defined conformations based around a repeating β-turn like structure, stabilised by (i, i-2) inter-residue hydrogen bonds, there is no indication of any secondary structure in the tetramer of the epimeric α- C- d-arabinofuranosyl carbohydrate amino acid, where the C-2 and C-5 substituents of the tetrahydrofuran ring are trans to each other.

Aqueous Ethylenediamine Dihydroxo Palladium(II): A Coordinating Agent for Low- and High-Molecular Weight Carbohydrates

An aqueous solution of [(en)Pd(OH)2] (Pd-en) forms 1,2and 1,3-diolato complexes on reaction with polyols. Three crystalline palladium(ii) complexes have been isolated and characterized with anhydroerythritol (AnEryt), 1,6-anhydro-b-d-glucose (1,6AnGlc, levoglucosan), and sucrose (Suc) as the polyol components, namely [(en)Pd(AnErytHy2)] 4 H2O (1), [(en)Pd(1,6AnGlc2,4Hy2)] H2O (2) and [(en)2Pd2(Suc1,3,3',4'Hy4)] 11 H2O (3). Pd-en acts as a coordinating solvent for cellulose; the polysaccharide anhydroglucose units (GlcC) form [(en)Pd(GlcC2,3Hy2)] entities on dissolution. The palladium-binding sites of the saccharides may be recognized by 13C NMR spectroscopy in the case of 1,2-diolic chelator groups, which exhibit a downfield, coordination-induced shift of the two diolato carbon atoms of about 10 ppm. Slightly yellow, viscous solutions of cellulose in Pd-en, which are largely insensitive to oxidative degradation, were characterized by light scattering (LS). Analysis of the chain conformation by LS supports the significance of chain stiffening by intramolecular interresidue hydrogen bonds of the type O6' ± H O2y in the molecularly dispersed and entirely metallated cellulose strands. The flexibility and energy of the hydrogen bond were investigated by density functional theory (DFT) calculations.

A solid phase approach to oligomers of carbohydrate amino-acids: Secondary structure in a trimeric furanose carbopeptoid

The synthesis of oligomers of a C-arabinofuranosyl carbohydrate amino acid on a polystyrene support functionalised with a Rink linker is reported. Cleavage from the solid support gives ready access to dimeric and trimeric carbopeptoids bearing a C-terminal carboxamide. Investigations into the solution structure of these novel carbopeptoids utilising 1H NMR indicate that they adopt well difined conformations based around a repeating β-turn like structure stabilised by (i, i-2) inter-residue hydrogen bonds.

The high degree of internal flexibility observed for an oligomannose oligosaccharide does not alter the overall topology of the molecule.

The conformational properties of oligosaccharides are important in determining their biological properties, such as recognition by proteins. The structural and dynamic properties of many oligosaccharides are poorly understood both because of a lack of experimental data (usually obtained from solution NMR parameters) and because of gross approximations frequently invoked in theoretical models. To characterise the oligomannose oligosaccharide Man,GlcNAc2 we have acquired a more extensive NMR data set and performed the first unrestrained molecular dynamics (MD) simulation in water of this large oligosaccharide (employing the GLYCAM_93 parameter set with the AMBER force field). Good agreement is seen between the computed dynamics data and the results of both an isolated spin pair (ISPA) analysis of short mixing time NOE data and NOE build-up curves for mixing times from 100 to 2000 ms. The number of experimental conformational constraints obtained in this study are in principle sufficient to fully define a rigid structure. The fact that this could not be done indicates a high degree of internal flexibility and/or the presence of multiple conformations about the glycosidic linkages. Independently, the same conclusions are reached from an analysis of the MD results. In addition, the theoretical results allow the overall topology of the molecule and its intra-molecular and solvent-mediated hydrogen bonding pattern to be defined. Extensive re-organisation of solvent and inter-residue hydrogen bonds is shown to be required for significant conformational changes to occur, resulting in relatively long life-times for distinct glycosidic linkage conformations, despite the high local flexibility of the glycosidic linkages. This factor is also seen in the overall topology of the molecule, where the considerable internal flexibility is not translated into gross changes in structure. The control exerted by the solvent over both the flexibility and overall topology of an oligosaccharide has important implications for recognition processes and for the conformational properties of glycans attached to glycoproteins.

Hydrogen-bonding and conformation of agarose in methyl sulfoxide and aqueous solutions investigated by 1H and 13C NMR spectroscopy

The conformation of agarose in dimethyl sulfoxide (Me 2SO) or in aqueous solutions has been studied by 1H and 13C NMR spectroscopy. Partial assignment of the 1H NMR spectrum of agarose in Me 2SO- d 6 has been obtained using 1D and 2D techniques. Coupling constant, chemical shift temperature dependence and exchange rate data for the hydroxyl protons have been used to establish the presence of intramolecular hydrogen bonds. The reported data show that the protons of HO-2 in the 3,6- anhydro-α- l-Gal p residue (A) and HO-4 in the β- d-Gal p residue (G) have a less rotational freedom and a higher thermal stability than the other hydroxyl protons. On the basis of the exchange rate data, obtained from 1D NOESY experiments with selective excitation of the residual water signal, an inter-residue hydrogen bond is proposed only for G HO-4 in Me 2SO, while the involvement of A HO-2 in the agarose-Me 2SO complex, recently reported, is suggested. The latter hypothesis is supported by the 13C NMR data obtained in Me 2SO- d 6, in a Me 2SO- d 6-D 2O mixture and in D 2O, which also show that a relatively small conformational rearrangement of the chain segments occurs in aqueous solution. Deuterium isotope effect data indicate the persistence in water of the inter-residue G HO-4 mediated hydrogen bond with the additional involvement of G HO-6. In addition, the negligible isotope effect on the C-2 atom of A would indicate that the corresponding OH group, although free from the agarose-Me 2SO complex, is not available for further strong interactions. The hydrogen bonding and conformation of agarose in methyl sulfoxide or in aqueous solutions were studied by NMR spectroscopy. Based on 1H NMR data, an inter-residue H-bond is proposed for HO-4 of β- d-Gal p in Me 2SO, while the involvement of HO-2 of 3,6- anhydro-α- l-Gal p in an agarose-Me 2SO complex is suggested. These hypotheses are supported by the 13C NMR data.

Methyl 2-O-α-D-Mannopyranosyl-β-D-glucopyranoside

The structure of the title compound, C 13 H 24 O 11 , has been determined. The torsion angles of the glycosidic linkage connecting the two sugar residues, φH (H1'-C1'-O2-C2) and ψH (C1'-O2-C2-H2), have values of -62.7 (2)° and -28.6 (2)°, respectively. The conformation in the crystal is similar to that obtained by energy minimization in vacuo using the HSEA (hardsphere exo-anomeric) force field. A chain of seven interresidue hydrogen bonds, involving all possible H-atom donors in the molecule is observed. The chain is terminated by a ring O atom as an acceptor.

The hydration of sucrose

The structural and dynamical features of the hydration of sucrose have been derived from a 500 ps molecular dynamics simulation with explicit water molecules. In order to obtain the degree and structure of the solvation of the sucrose solute, radial atomic pair distribution functions have been calculated between selected solute atoms and the water molecules. The analysis provides a molecular hydration number of 37.6 water molecules in the first hydration shell. If the ‘hydration criterion’ is restricted to include oxygen-oxygen distances less than 2.8 Å, an average hydration number of 7 is obtained, which is close to that derived experimentally from viscosity and apparent molar volume. This indicates that the firmly hydrogen bonded water molecules have more impact on the macroscopic properties than the shielding effect formed by the first hydration shell. Both the radial and orientational hydration of acetal and hydroxyl oxygens have been fully characterized. The analysis reveals significant differences between the glycosidic oxygen and the ring oxygen atoms. It also shows that the water structure around the three secondary hydroxyl groups of the pyranosyl moiety is more structured than around the rest of the molecule. This indicates a more perfect hydration of this relatively rigid part of sucrose. The residence times for polar water molecules around the sucrose solute were also characterized. Whereas typical values are in the order of 1 to 2 ps, some extremely long residence times of about 30 ps may occur in the vicinity of the O-3 hydroxyl group of the fructofuranosyl moiety. Extension of the analysis to significant bridging water molecules points towards the existence of two cases (O-2g … Ow … O-3f and O-2g … Ow … O-1f) being populated more than 41% and 66% of the time. In comparison, the direct interresidue hydrogen bond O-2g … O-1f is populated less than 4% of the time. The bridging water between O-2g and O-3f is found in the crystalline complex between sucrose and a lentil lectin. In an aqueous environment the ability of sucrose to establish these water-mediated hydrogen bonds between its two moieties may be relevant in explaining the oversaturation range which prevails before nucleation occurs. It may also have significant implications as far as the sweet-taste elicitation mechanism is concerned.