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PubMed1990

Conformation and dynamics of the deoxyribose rings of a (nogalamycin)2-d (5'-GCATGC)2 complex studied in solution by 1H-n.m.r. spectroscopy.

The conformation and dynamics of the deoxyribose rings of a (nogalamycin)2-d(5'-GCATGC)2 complex have been determined from an analysis of 1H-1H vicinal coupling constants and sums of coupling constants (J1'-2',J1'-2",epsilon 1', epsilon 2' and epsilon 2") measured from one-dimensional n.m.r. spectra and from H-1'-H-2' and H-1'-H-2" cross-peaks in high-resolution phase-sensitive two-dimensional correlation spectroscopy (COSY) and double-quantum-filtered correlation spectroscopy (DQF-COSY) experiments. The value of J3'-4' has also been estimated from the magnitude of H-3'-H-4' cross-peaks in DQF-COSY spectra and H-1'-H-4' coherence transfer cross-peaks in two-dimensional homonuclear Hartman-Hahn spectroscopy (HOHAHA) spectra. The data were analysed, in terms of a dynamic equilibrium between North (C-3'-endo) and South (C-2'-endo) conformers, by using the graphical-analysis methods described by Rinkel & Altona [(1987) J. Biomol. Struct. Dyn. 4,621-649]. The data reveal that the sugars of the 2C-5G and 3A-4T base-pairs, which form the drug-intercalation site, have strikingly different properties. The deoxyribose rings of the 2C-5G base-pair are best described in terms of an equilibrium heavily weighted in favour of the C-2'-endo geometry (greater than 95% 'S'), with a phase angle, P, lying in the range 170-175 degrees and amplitude of pucker between 35 and 40 degrees, as typically found for B-DNA. For the deoxyribose rings of the 3A-4T base-pair, however, the analysis shows that, for 3A, the C-2'-endo and C3'-endo conformers are equally populated, whereas a more limited data set for the 4T nucleotide restricts the equilibrium to within 65-75% C-2'-endo. The deoxyribose rings of the 1G-6C base-pair have populations of 70-80% C-2'-endo, typical of nucleotides at the ends of a duplex. Although drug-base-pair stacking interactions are an important determinant of the enhanced duplex stability of the complex [Searle, Hall, Denny, & Wakelin (1988) Biochemistry 27, 4340-4349], the current findings make it clear that the same interactions can be associated with considerable variations in the degree of local structural dynamics at the level of the sugar puckers.

Base Sequence↗
PubMed1991

Nuclear magnetic resonance investigations of calcium antagonist drugs. II: Conformational and dynamic features of verapamil in [2H6]DMSO.

Conformational features of verapamil in [2H6]DMSO have been delineated by measuring 13C and 1H NMR parameters. Spin-lattice relaxation rates were interpreted within the frame of an extended alkane chain with segmental motions hampered by the aromatic substituents at both ends. The effective correlation times were all evaluated in the range 0.16-0.22 ns at 293 K. The aromatic rings were found to lie somewhat out-of-plane with the alkane chain. The NMR data were used to construct a Dreiding model of the most probable spatial arrangement and a molecular modeling system was utilized to represent the "preferred" conformation of verapamil in solution.

Calcium Channel Blockers↗
PubMed1983

Pharmacological, conformational and dynamic properties of cycloleucine-2 analogues of oxytocin and [1-penicillamine]oxytocin.

The solid phase syntheses of [2-cycloleucine] oxytocin and [1-penicillamine, 2-cycloleucine] oxytocin are reported. [1-Penicillamine, 2-cycloleucine] oxytocin is an oxytocin antagonist exhibiting no in vitro oxytocic activity. In the in vitro oxytocic assay, [1-penicillamine, 2-cycloleucine] oxytocin has a pA2 value of 6.70 +/- 0.08. [2-Cycloleucine]-oxytocin is a full oxytocin agonist exhibiting 4.9 +/- 0.5 U/mg of oxytocic activity. Neither compound possesses any measurable agonist or antagonist activity in the rat pressor assay. Carbon-13 nuclear magnetic resonance chemical shift parameters and spin-lattice relaxation times (T1) of the antagonist, [1-penicillamine, 2-cycloleucine] oxytocin, indicate that the antagonist exhibits similar conformational and dynamic properties as other oxytocin inhibitors previously studied. The carbon-13 nuclear magnetic resonance shift parameters and spin-lattice relaxation times (T1) of the oxytocin agonist, [2-cycloleucine] oxytocin, indicate that the agonist exhibits similar conformational and dynamic properties as oxytocin. These results are discussed in terms of the different receptor requirements for agonist and antagonist activities. It appears that there are different structural and conformational requirements at the 2-position for oxytocic agonist and antagonist activities.

Animals↗
PubMed2006

Conformation and dynamics changes of bacteriorhodopsin and its D85N mutant in the absence of 2D crystalline lattice as revealed by site-directed 13C NMR.

13C NMR spectra of [3-(13)C]Ala- and [1-(13)C]Val-labeled D85N mutant of bacteriorhodopsin (bR) reconstituted in egg PC or DMPC bilayers were recorded to gain insight into their secondary structures and dynamics. They were substantially suppressed as compared with those of 2D crystals, especially at the loops and several transmembrane alphaII-helices. Surprisingly, the 13C NMR spectra of [3-(13)C]Ala-D85N turned out to be very similar to those of [3-(13)C]Ala-bR in lipid bilayers, in spite of the presence of globular conformational and dynamics changes in the former as found from 2D crystalline preparations. No further spectral change was also noted between the ground (pH 7) and M-like state (pH 10) as far as D85N in lipid bilayers was examined, in spite of their distinct changes in the 2D crystalline state. This is mainly caused by that the resulting 13C NMR peaks which are sensitive to conformation and dynamics changes in the loops and several transmembrane alphaII-helices of the M-like state are suppressed already by fluctuation motions in the order of 10(4)-10(5) Hz interfered with frequencies of magic angle spinning or proton decoupling. However, 13C NMR signal from the cytoplasmic alpha-helix protruding from the membrane surface is not strongly influenced by 2D crystal or monomer. Deceptively simplified carbonyl 13C NMR signals of the loop and transmembrane alpha-helices followed by Pro residues in [1-(13)C]Val-labeled bR and D85N in 2D crystal are split into two peaks for reconstituted preparations in the absence of 2D crystalline lattice. Fortunately, 13C NMR spectral feature of reconstituted [1-(13)C]Val and [3-(13)C]Ala-labeled bR and D85N was recovered to yield characteristic feature of 2D crystalline form in gel-forming lipids achieved at lowered temperatures.

Amino Acid Substitution↗
PubMed2006

G protein-coupled receptors sense fluid shear stress in endothelial cells.

Hemodynamic shear stress stimulates a number of intracellular events that both regulate vessel structure and influence development of vascular pathologies. The precise molecular mechanisms by which endothelial cells transduce this mechanical stimulus into intracellular biochemical response have not been established. Here, we show that mechanical perturbation of the plasma membrane leads to ligand-independent conformational transitions in a G protein-coupled receptor (GPCR). By using time-resolved fluorescence microscopy and GPCR conformation-sensitive FRET we found that stimulation of endothelial cells with fluid shear stress, hypotonic stress, or membrane fluidizing agent leads to a significant increase in activity of bradykinin B2 GPCR in endothelial cells. The GPCR conformational dynamics was detected by monitoring redistribution of GPCRs between inactive and active conformations in a single endothelial cell under fluid shear stress in real time. We show that this response can be blocked by a B(2)-selective antagonist. Our data demonstrate that changes in cell membrane tension and membrane fluidity affect conformational dynamics of GPCRs. Therefore, we suggest that GPCRs are involved in mediating primary mechanochemical signal transduction in endothelial cells. We anticipate our experiments to be a starting point for more sophisticated studies of the effects of changes in lipid bilayer environment on GPCR conformational dynamics. Furthermore, because GPCRs are a major target of drug development, a detailed characterization of mechanochemical signaling via the GPCR pathway will be relevant for the development of new antiatherosclerosis drugs.

Animals↗
PubMed2000

Conformation and dynamics of heparin and heparan sulfate.

The glycosaminoglycans heparin and heparan sulfate contain similar structural units in varying proportions providing considerable diversity in sequence and biological function. Both compounds are alternating copolymers of glucosamine with both iduronate- and glucuronate-containing sequences bearing N-sulfate, N-acetyl, and O-sulfate substitution. Protein recognition of these structurally-diverse compounds depends upon substitution pattern, overall molecular shape, and on internal mobility. In this review particular attention is paid to the dynamic aspects of heparin/heparan sulfate conformation. The iduronate residue possesses an unusually flexible pyranose ring conformation. This extra source of internal mobility creates special problems in rationalization of experimental data for these compounds. We present herein the solution-state NMR parameters, fiber diffraction data, crystallographic data, and molecular modeling methods employed in the investigation of heparin and heparan sulfate. Heparin is a useful model compound for the sulfated, protein-binding regions of heparan sulfate. The literature contains a number of solution and solid-state studies of heparin oligo- and polysaccharides for both isolated heparin species and those bound to protein receptors. These studies indicate a diversity of iduronate ring conformations, but a limited range of glycosidic linkage geometries in the repeating disaccharides. In this sense, heparin exhibits a well-defined overall shape within which iduronate ring forms can freely interconvert. Recent work suggests that computational modeling could potentially identify heparin binding sites on protein surfaces.

Animals↗
PubMed1996

Molecular dynamics-derived conformation and intramolecular interaction analysis of the N-acetyl-9-O-acetylneuraminic acid-containing ganglioside GD1a and NMR-based analysis of its binding to a human polyclonal immunoglobulin G fraction with selectivity for O-acetylated sialic acids.

The influence of 9-O-acetylation of GD1a, yielding GD1a (eNeu5,9Ac2) with a 9-O-acetylated sialic acid moiety linked to the outer galactose residue, on the spatial extension and mobility of the carbohydrate chain and on recognition by a natural human antibody is analysed. To study a potential impact of the O-acetyl group on the overall conformation of the carbohydrate chain, molecular dynamics (MD) simulations of oligosaccharide chain fragments of increasing length starting from the non-reducing end have been carried out for the first time in this study. They revealed a considerable loss in chain flexibility after addition of the internal N-acetylneuraminic acid onto the chain. Besides MD calculations with different dielectric constants, the conformational behaviour of the complete oligosaccharide chain of the 9-O-acetylated GD1a ganglioside was simulated in the solvents water and dimethyl sulfoxide. These solvents were also used in NMR measurements. The results of this study indicate that 9-O-acetylation at the terminal sialic acid does not influence the overall conformation of the ganglioside. An extended interaction analysis of energetically minimized conformations of GD1a (eNeu5,9Ac2) and GD1a, obtained during molecular dynamics simulations, allowed assessment of the influence of the different parts of the saccharide chains on spatial flexibility. Noteworthy energetic interactions, most interestingly between the 9-O-acetyl group and the pyranose ring of N-acetylgalactosamine, were ascertained by the calculations. However, the strength of this interaction does not force the ganglioside into a conformation, where the 9-O-acetyl group is no longer accessible. Binding of GD1a (eNeu5,9Ac2) to proteins, which are specific for 9-O-acetylated sialic acids, should thus at least partially be mediated by the presence of this group. To experimentally prove this assumption, a NMR study of 9-O-acetylated GD1a in the presence of an affinity-purified polyclonal IgG fraction from human serum with preferential binding to 9-O-acetylated sialic acid was performed. The almost complete disappearance of the intensity of the 9-O-acetyl methyl signal of the GD1a (eNeu5,9Ac2) clearly indicates that the assumed interaction of the 9-O-acetyl group with the human protein takes place.

Acetylation↗
PubMed1997

Solution conformation and dynamics of a tetrasaccharide related to the Lewix(X) antigen deduced by 1H NMR NOESY, ROESY, and T-ROESY measurements.

The conformational and dynamical features of a Le(X) tetrasaccharide analogue GalNAc (alpha 1-3)Gal(beta 1-4)[Fuc(alpha 1-3)]Glc(beta OMe) 1 have been studied through 1H NMR relaxation measurements. The results indicate that the different glycosidic linkages of 1 present distinct conformational flexibility in solution. In addition, the use of T-ROESY experiments in conformational analysis of oligosaccharides is explored emphasizing its scope and limitations.

Carbohydrate Conformation↗
PubMed1984

Deoxyguanosine-deoxyadenosine pairing in the d(C-G-A-G-A-A-T-T-C-G-C-G) duplex: conformation and dynamics at and adjacent to the dG X dA mismatch site.

Nuclear magnetic resonance (NMR) has been used to monitor the conformation and dynamics of the d-(C1-G2-A3-G4-A5-A6-T6-T5-C4-G3-C2-G1) self-complementary dodecanucleotide (henceforth called 12-mer GA) that contains a dG X dA purine-purine mismatch at position 3 in the sequence. These results are compared with the corresponding d(C-G-C-G-A-A-T-T-C-G-C-G) dodecamer duplex (henceforth called 12-mer) containing standard Watson-Crick base pairs at position 3 [Patel, D.J., Kozlowski, S.A., Marky, L.A., Broka, C., Rice, J.A., Itakura, K., & Breslauer, K.J. (1982) Biochemistry 21, 428-436]. The dG X dA interaction at position 3 was monitored at the guanosine exchangeable H-1 and nonexchangeable H-8 protons and the nonexchangeable adenosine H-2 proton. We demonstrate base-pair formation between anti orientations of the guanosine and adenosine rings on the basis of nuclear Overhauser effects (NOE) observed between the H-2 proton of adenosine 3 and the imino protons of guanosine 3 (intra base pair) and guanosines 2 and 4 (inter base pair). The dG(anti) X dA(anti) pairing should result in hydrogen-bond formation between the guanosine imino H-1 and carbonyl O-6 groups and the adenosine N-1 and NH2-6 groups, respectively. The base pairing on either side of the dG X dA pair remains intact at low temperature, but these dG X dC pairs at positions 2 and 4 are kinetically destabilized in the 12-mer GA compared to the 12-mer duplex. We have estimated the hydrogen exchange kinetics at positions 4-6 from saturation-recovery measurements on the imino protons of the 12-mer GA duplex between 5 and 40 degrees C. The measured activation energies for imino proton exchange in the 12-mer GA are larger by a factor of approximately 2 compared to the corresponding values in the 12-mer duplex. This implies that hydrogen exchange in the 12-mer GA duplex results from a cooperative transition involving exchange of several base pairs as was previously reported for the 12-mer containing a G X T wobble pair at position 3 [Pardi, A., Morden, K.M., Patel, D.J., & Tinoco, I., Jr. (1982) Biochemistry 21, 6567-6574]. We have assigned the nonexchangeable base protons by intra and inter base pair NOE experiments and monitored these assigned markers through the 12-mer GA duplex to strand transition.(ABSTRACT TRUNCATED AT 400 WORDS)

Hydrogen↗
PubMed2004

Conformational analysis and dynamics of mannobiosides and mannotriosides using Monte Carlo/stochastic dynamics simulations.

The conformation and dynamics of alpha-(1-->2)-mannobioside, alpha-(1-->6)-mannobioside, and of the trisaccharide alpha-Man-(1-->2)-alpha-Man-(1-->6)-alpha- Man-OMe were studied using Monte Carlo/stochastic dynamics (MC/SD) simulations, the AMBER* force field, and the GB/SA implicit water solvation model. The results are in agreement with available experimental data.

Carbohydrate Conformation↗
PubMed1997

Solution conformation and dynamics of an extracellular polysaccharide isolated from Bradyrhyzobium as deduced from 1H-NMR off resonance ROESY and 13C-NMR relaxation measurements.

The conformational and dynamical features of an extracellular branched deacetylated polysaccharide isolated from Bradyrhizobium (Chamaecytisus proliferus) have been investigated by homo and heteronuclear NMR methods. 1H-NMR cross relaxation rates have been obtained for this polysaccharide through regular NOESY and ROESY spectra as well as by modern off resonance ROESY techniques. Local proton-proton correlation times as well as interproton distances have been obtained. 13C-NMR relaxation parameters (T1, T2, NOE) have also been measured at two different magnetic fields and interpreted using different approximations based on the Lipari and Szabo model free approach. The analysis of the data indicates the existence of important flexibility for the different linkages of the polysaccharide. Motions in the range of several ns contribute to the relaxation of the macromolecule, although faster internal motions in the 600-800 ps time scales are also present. These time scales indicate that segmental motions as well as internal motions around the glycosidic linkages are the major sources of relaxation for this molecule at 299 K.

Carbohydrate Conformation↗
PubMed1991

Solution conformation and dynamics of the octadeoxy-nucleotide d(CACTAGTG)2: a multinuclear n.m.r. relaxation study.

The conformation and internal dynamics of the octadeoxynucleotide d(CACTAGTG)2 have been examined by 1H- and 13C-n.m.r. relaxation. All the non-exchangeable protons, the seven phosphate resonances, and most of the 13C resonances of the proton-bearing carbons have been assigned by conventional two-dimensional n.m.r. methods. The average conformations of each nucleotide have been determined using time-dependent one-dimensional n.O.e.'s and 3JHH values derived from both NOESY and 2-quantum-filtered COSY experiments. All glycosidic torsion angles are anti, and in the range -95 to 125 degrees, in which the pyrimidines have a significantly larger angle than the purines. All sugars were found mainly (greater than 80%) in the conformation range C-2'endo to C-3'exo. The DNA fragment is within the B-family of conformations. The cytosine H-6-H-5 vectors move with an apparent correlation time of 3 ns at 25 degrees. Cross-relaxation rate constants for the H-1'-H-2b vectors and some H-2a-H-2b and H-2a-H-3' vectors were measured, from which order parameters were determined. The order parameters are all in the range 0.7-0.9, which is consistent with only moderate internal mobility on the sub-ns time scale. The (1H)-13C n.O.e. and the spin-lattice relaxation rate constant show that the terminal residues are relatively more mobile than the internal residues, and that the C-2'-H and C-3'-H vectors move with order parameters of 0.6-0.75.

Base Sequence↗
PubMed2000

Comparison of the conformation and dynamics of a polysaccharide and of its isolated heptasaccharide repeating unit on the basis of nuclear Overhauser effect, long-range C-C and C-H coupling constants, and NMR relaxation data.

A comparison of the conformation and dynamics of the cell wall polysaccharide of S. mitis J22 and the heptasaccharide repeating unit made from this polysaccharide was performed on the basis on nmr data. We have previously reported a model for this highly flexible polysaccharide in which four residues of the antigenic epitope adopt a defined conformation as do the two residues of the lectin-binding epitope. These domains are connected by a 6-substituted galactofuranoside residue that acts as a flexible hinge and the repeating subunits are joined by phosphodiester linkages that provide further flexibility. Homonuclear nuclear Overhauser effect (NOE) and long-range C-C and C-H scalar coupling constants measured in uniform (13)C-labeled samples of the polysaccharide and heptasaccharide were very similar, indicating a similar conformational average in solution. Significant differences in the solution dynamics were found from the heteronuclear relaxation data, T(1), T(1 rho), and NOE, which reflect the faster molecular tumbling of the heptasaccharide. Internal motions occurring on a picosecond time scale are relatively uniform along the polymer while dynamics on the time scale longer than a few nanoseconds is characteristic of hinge motion.

Carbohydrate Conformation↗
PubMed1991

Relation between stability, dynamics and enzyme activity in 3-phosphoglycerate kinases from yeast and Thermus thermophilus.

3-Phosphoglycerate kinases from yeast and the extreme thermophilic bacterium Thermus thermophilus HB8 have been used as models for investigating the relationship between stability, dynamics and activity. It was found that while at a given temperature the thermophilic protein is more stable, its conformational dynamics as measured by the ability of acrylamide to quench the fluorescence of a buried tryptophan as well as its specific activity, are both lower than for the mesophilic protein. As the temperature is increased, the thermodynamic stability of the thermophilic protein approaches that of the mesophilic protein at its working temperature. Its conformational dynamics and specific activity however were both shown to increase, until at the physiologically operational temperature, they become similar to those of the mesophilic enzyme at its operational temperature. These results confirm the proposal that a direct relationship and balance holds between thermodynamic stability, dynamics and specific activity in globular proteins. They demonstrate also the constraining effect of increased stability upon conformational dynamics and enzyme activity.

Acrylamide↗
PubMed1996

Dynamic chain conformations in dimyristoyl glycerol-dimyristoyl phosphatidylcholine mixtures. 2H-NMR studies.

The dynamic molecular lipid chain conformations in fully hydrated dimyristoyl phosphatidylcholine (DMPC)-dimyristoyl glycerol (DMG) mixtures have been investigated by 2H-NMR spectroscopy of the individual lipid components, the sn-2 chains of which were perdeuterated or, in the case of DMG, specifically deuterated at the C-2 position. Mixtures of compositions corresponding to the three different regions of the binary phase diagram in which the fluid phase is lamellar (DMPC:DMG 70:30 mol/mol), inverted hexagonal (DMPC:DMG 45:55 and 40:60 mol/mol), or isotropic (DMPC:DMG 20:80 mol/mol) were investigated. The gel phase in all three regions of the phase diagram has a lamellar structure, with the lipid chains rotating about the molecular long axis but executing only limited angular excursions. In the fluid lamellar phase of the 70:30 mol/mol DMPC-DMG mixture the profile of segmental chain flexibility is similar to that in single-component phospholipid bilayers and is characterized by an order parameter plateau for both lipid components. The chain order of the DMPC component is greater than in bilayers of DMPC alone and is also greater than that of the DMG component. In the inverted hexagonal phase of the 45:55 mol/mol DMPC-DMG mixture the chain flexibility profile is characterized by more widely spaced segmental order parameters off the plateau region. The intrinsic degree of chain order in the inverted hexagonal phase is less than in the lamellar phase of the 70:30 mol/mol mixture, and the difference in chain order between the DMPC and DMG components is reduced relative to that in the lamellar phase. The unique conformational features at the C-2 position of the sn-2 chain that characterize bilayers of diacyl phospholipids are found also for the diacylglycerol molecules in the fluid lamellar phase and most probably also in the inverted hexagonal phase. The DMG molecules are therefore integrated in the membrane (or nonlamellar lipid phase) in a configuration that is similar to that of the phospholipids and different from the crystal structure of diacylglycerols.

Deuterium↗
PubMed1982

Molecular dynamics and conformation in the gel and liquid-crystalline phases of phosphatidylethanolamine bilayers.

Solid-state deuterium and carbon-13 nuclear magnetic resonance (NMR) spectra have been used to study the molecular dynamics and conformation of dipalmitoylphosphatidylethanolamine (DPPE) in both the gel (L beta) and liquid-crystalline (L alpha) phases. For this purpose DPPE was labeled with 13C in the carbonyl group of the sn-2 chain and with 2H at three different positions--4, 8, and 12--of the sn-2 chain, at the 2 position of the glycerol backbone, and at the 1 position of the ethanolamine head group. The 13C carbonyl and 2H chain spectra indicate that in the gel phase the DPPE molecules are diffusing about their long axes at rates of 10(5)-10(6) s-1 and the acyl chains are in an approximately all-trans conformation. The glycerol backbone spectra suggest that the backbone is in a gauche conformation in the gel state, rather than a trans conformation such as found in single crystals. The head group spectra in the gel phase are broad, featureless lines of about 20-kHz width. At the L beta leads to L alpha phase transition several changes take place. As is well-known, the chains disorder, and fast long-axis rotational diffusion begins, which results in the sharp, axially symmetric L alpha phase 2H spectra, which are a factor of 2 narrower than those observed in the L beta phase. The head group spectra also sharpen substantially at the transition, although their total width remains approximately constant. The invariance of the spectral width suggests that the average head group conformation is similar in both phases. However, the sharper spectra seen in the L alpha phase indicate that the rates of the head group motions in this phase are at least 3 orders of magnitude faster than those in the L beta phase. Thirdly, the 2H spectra of the glycerol backbone labeled DPPE narrow by a factor of about 4, and we believe this is due to a conformational change in this region of the molecule. Consistent with this interpretation is the fact that the powder pattern exhibited by the sn-2 13C = O in the L beta phase collapses to an isotropic-like line at the phase transition.

Gels↗
PubMed1989

Effects of glycosylation on the conformation and dynamics of O-linked glycoproteins: carbon-13 NMR studies of ovine submaxillary mucin.

Carbon-13 NMR spectroscopic studies of native and sequentially deglycosylated ovine submaxillary mucin (OSM) have been performed to examine the effects of glycosylation on the conformation and dynamics of the peptide core of O-linked glycoproteins. OSM is a large nonglobular glycoprotein in which nearly one-third of the amino acid residues are Ser and Thr which are glycosylated by the alpha-Neu-NAc(2-6)alpha-GalNAc- disaccharide. The beta-carbon resonances of glycosylated Ser and Thr residues in intact and asialo mucin display considerable chemical shift heterogeneity which, upon the complete removal of carbohydrate, coalesces to single sharp resonances. This chemical shift heterogeneity is due to peptide sequence variability and is proposed to reflect the presence of sequence-dependent conformations of the peptide core. These different conformations are thought to be determined by steric interactions of the GalNAc residue with adjacent peptide residues. The absence of chemical shift heterogeneity in apo mucin is taken to indicate a loss in the peptide-carbohydrate steric interactions, consistent with a more relaxed random coiled structure. On the basis of the 13C relaxation behavior (T1 and NOE) the dynamics of the alpha-carbons appear to be unique to each amino acid type and glycosylation state, with alpha-carbon mobilities decreasing in the order Gly greater than Ala = Ser greater than Thr much greater than monoglycosylated Ser/Thr approximately greater than disaccharide linked Ser/Thr.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗