Biomedical subjects

K K Bhandary

Publications and source records attributed to K K Bhandary.

At least 19 recordsLinked to original sources

PubMed1994

A new class of substituted 1,2,4-triazolo-1,3,4-thiadiazepines.

A series of 3-aryloxymethyl-(5-nitro-2-furyl)-6-phenyl-1,2,4- triazolo[3,4-b][1,3,4]thiadiazepine compounds have been synthesized recently by a new route. Reported here are the structures of two such compounds with para-substituted aryloxymethyl groups: one has a chloro group, 3-(4-chlorophenyl-oxymethyl)-8-(5-nitro-2-furyl)-6-phenyl-1,2,4- triazolo[3,4-b][1,3,4]thiadiazepine, C22H14C1N5O4S, TD1, and the other a methyl group, 3-(p-tolyloxy-methyl)-8-(5-nitro-2-furyl)-6-phenyl-1,2,4- triazolo-[3,4-b][1,3,4]thiadiazepine, C23H17N5O4S, TD7. The nitrofuryl and phenyl groups on the thiadiazepine ring are each found to adopt a similar conformation in the two structures, whereas the aryloxymethyl substituents on the triazole rings are conformationally different from each other. Each thiadiazepine ring adopts a boat conformation with the S atom at the apex. The interplanar angle between the triazole ring and the thiadiazepine ring is 30 degrees for both compounds. The conformation of the aryloxy-methyl group is dependent on the intermolecular interactions that arise as a result of the polarity of the para substituent. The Cl group in TD1 is involved in a C-Cl...O non-bonded interaction with a Cl...O distance of 3.100 (3) A and a C-Cl...O angle of 138.4 (1) degree. TD7 has a stacking interaction involving the nitrofuryl groups.

Crystallography, X-Ray↗

PubMed1994

Crystal structure of cyclo(Pro-Gly)3:Li complex: a model for ion transport by cyclo(Pro-Gly)3.

The crystal structure of cyclo(Pro-Gly)3 (PG3) complex with LiSCN (C22H30N7O6SLi) has been solved by x-ray diffraction. The crystals belong to the space group R3 in the hexagonal setting with unit cell parameters of a = 12.581(1), c = 29.705(3) A, V = 4072.0 A3, Z = 6, M(r) = 527.53, Dc = 1.23 g/cm3. The crystal structure was solved by direct methods using the program SHELXS-86 and refined to an R value of 5.3% for 1645 reflections (I > 2 sigma I). There are two conformers in the crystal structure. One conformer has three carbonyls on one side and three on the other side of the peptide plane. The other conformer has all six of the carbonyls on the same side of the peptide plane. Both of these conformers bind independently to a Li ion. Based on the conformers of the Li complex and other reported ion complexes formed by PG3, we propose a model for the transport of ions across the lipid membrane. The features of the model are as follows: (1) PG3 forms a hexameric stack in a lipid bilayer when complexing and transporting metal ions. (2) It undergoes a conformational flipping in order pass the ion along the channel. The energy required for the conformational change involved in the flipping of the PG3 molecule may be provided by the applied potential during ion transport.

Biological Transport, Active↗

PubMed1994

Structural characteristics of diproline: a new crystal form of tBoc-Pro-Pro-OH.

The structure of a new crystalline form of tBoc-Pro-Pro-OH (C15 H24 N2 O5) has been determined. The crystals were monoclinic, P2(1), a = 14.667(5), b = 16.600(4), c = 15.502(3) A, beta = 117.84(2) degrees, V = 3337.2 A3 and Z = 8, Dc = 1.24 g/cm3. There are four molecules in the asymmetric unit, each displaying polyproline-type structure but differing in the proline pucker. All four molecules display a twist conformation in the first proline ring, with molecules A, B and C being beta gamma T (P approximately 183 degrees, tau approximately 33 for A and B, tau approximately 18 for C) and molecule D between gamma beta T and gamma E (P = 10 degrees, tau approximately 38). The second residue of all four molecules has an envelope conformation. Molecules A and B display an alpha E conformation (P approximately 126 degrees, tau approximately 25) and molecules C and D display a beta E conformation (P approximately 168 degrees, tau approximately 37). The molecules are hydrogen-bonded (O...OH), forming helical channels along the alpha-axis.

Amino Acid Sequence↗

PubMed1993

Peptide design 3(10)-helical conformation of a linear pentapeptide containing two dehydrophenylalanines, Boc-Gly-delta ZPhe-Leu-delta ZPhe-Ala-NHCH3.

alpha,beta-Dehydroamino acids are expected to provide conformational constraint to the peptide backbone. A pentapeptide containing two dehydrophenylalanines (delta ZPhe) separated by one L-amino acid has been synthesized and its solid state conformation determined. The pentapeptide, Boc-Gly-delta ZPhe-Leu-delta ZPhe-Ala-NHCH3, crystallizes from aqueous methanol in the orthorhombic space group P2(1)2(1)2(1). There are four formula units, C35H46N6O7, in a unit cell of dimensions a = 10.155(3), b = 15.175(1), and c = 23.447(2) A, at room temperature. The structure was solved by direct methods program, SIR88, and refined to a final R = 0.038 based on 3049 reflections with I > 2 sigma (I). All the peptide links are trans and the backbone conformation of the pentapeptide can be described as a 3(10)-helix, with mean phi,psi values of -65.1 degrees and -22.8 degrees (the value is averaged over the first four residues). There are four intramolecular 4-->1 type hydrogen bonds characteristic of 3(10)-type helices. In the crystal, the helices are held together by intermolecular N-H...O = C head-to-tail and lateral hydrogen bonding between symmetry related molecules. This mode of packing is similar to the packing motifs observed so often in other oligopeptides that adopt a 3(10)-helical structure.

Amino Acid Sequence↗

PubMed1993

Conformational mobility in cyclic oligopeptides.

Analysis of two isomeric cyclic hexapeptides of composition (Asp, Arg, Gly2, Pro, D-Pro) by a nuclear Overhauser effect constrained distance geometry conformation search yielded a narrowly defined backbone conformation for one and considerable ambiguity about the conformation in part of the other. Preliminary 13C relaxation studies of these peptides suggest that it is possible that this difference may correspond to a physical difference in internal mobility. In connection with this observation, other experimental evidence bearing on the backbone conformational mobility of cyclic oligopeptides with 4-10 residues, frequently considered to have well-defined backbones, is reviewed. Conformational heterogeneity involving rotation of a peptide bond plane relative to the overall ring plane is identified as a common phenomenon. Nuclear magnetic resonance line-shape studies at temperatures down to 200 K can detect backbone motions with activation free energy barriers down to about 10 kcal/mole, but conformational exchange with lower barriers, though detectable in other ways, will not be obvious from nmr spectra alone.

Amino Acid Sequence↗

PubMed1993

Structural characteristics of human salivary statherin: a model for boundary lubrication at the enamel surface.

A three-dimensional structural model for salivary statherin in aqueous phase has been developed using structure prediction, circular dichroism, molecular modeling, and mechanics. The relevant structural features of statherin are N-terminal helix segment connected to a long poly-L-proline type II segment, which is followed by a short extended structure. Using this model, the hydroxyapatite binding ability of statherin has been explained. The hydroxyapatite binding region is comprised of the N-terminal acidic residues (Asp-pSer-pSer-Glu-Glu) and Glu-26, which are clustered together in space. Partial conformational unfolding and oriented aggregation of several statherin molecules at the enamel surface provides an amphipathic film that is responsible for the boundary lubrication exhibited by statherin.

Actinomyces viscosus↗

PubMed1992

Crystal structure and conformation of a highly constrained linear tetrapeptide Boc-Leu-dehydro Phe-Ala-Leu-OCH3.

The conformation of a tetrapeptide containing a dehydro amino acid, delta ZPhe, in its sequence has been determined in the crystalline state using X-ray crystallographic techniques. The tetrapeptide, Boc-Leu-delta ZPhe-Ala-Leu-OCH3, crystallizes in the orthorhombic space group P2(1)2(1)2(1) with four molecules in a unit cell of dimensions a = 11.655(1) A, b = 15.698(6) A and c = 18.651(3) A V = 3414.9 A and Dcalc = 1.12 g/cm-3. The asymmetric unit contains one tetrapeptide molecule, C30H46N4O7, a total of 41 nonhydrogen atoms. The structure was determined using the direct methods program SHELXS86 and refined to an R-factor of 0.049 for 3347 reflections (I3.0(I). The linear tetrapeptide in the crystal exhibits a double bend of the Type III-I, with Leu1 (phi = -54.1 degrees, psi = -34.5 degrees) and delta ZPhe2 (phi = -59.9 degrees, psi = -17.1 degrees) as the corner residues of Type III turn and delta ZPhe2 (phi = -59.9 degrees, psi = -17.1 degrees) and Ala3 (phi = -80.4 degrees, psi = 0.5 degrees) residues occupying the corners of Type I turn, with delta ZPhe as the common residue in the double bend. The turn structures are further stabilized by two intramolecular 4----1 type hydrogen bonds.

Amino Acid Sequence↗

PubMed1991

Statherin: a major boundary lubricant of human saliva.

The lubricating properties of human submandibular-sublingual salivary fractions were examined using a servohydraulic model of mandibular movement. Fractions containing statherin exhibited a strong tendency to boundary lubrication. The lubricity of purified statherin was confirmed and compared to the amphipathic molecules gramacidin S and sodium dodecyl sulfate. Contact angle measurements of statherin paralleled the other amphipathic molecules. The helical content of statherin increased in trifluoroethanol indicating the presence of amphipathic helical regions. CD studies and hydrophobic moment calculations indicated that statherin adopts an amphipathic helical conformation at the N-terminus. An energy-minimized model of the polar N-terminal residues 1-15 suggested that this domain could be positioned in space to interact with a hydroxyapatite substrate. These data imply that under appropriate conditions statherin may display an amphipathic nature which enables it to function as a boundary lubricant on enamel.

Adult↗

PubMed1991

Role of peptide backbone conformation on biological activity of chemotactic peptides.

To investigate the role of peptide backbone conformation on the biological activity of chemotactic peptides, we synthesized a unique analog of N-formyl-Met-Leu-Phe-OH incorporating the C alpha,alpha disubstituted residue, dipropylglycine (Dpg) in place of Leu. The conformation of the stereochemically constrained Dpg analog was examined in the crystalline state by x-ray diffraction and in solution using NMR, IR, and CD methods. The secretagogue activity of the peptide on human neutrophils was determined and compared with that of a stereochemically constrained, folded type II beta-turn analog incorporating 1-aminocyclohexanecarboxylic acid (Ac6c) at position 2 (f-Met-Ac6c-Phe-OMe), the parent peptide (f-Met-Leu-Phe-OH) and its methyl ester derivative (f-Met-Leu-Phe-OMe). In the solid state, the Dpg analog adopts an extended beta-sheet-like structure with an intramolecular hydrogen bond between the NH and CO groups of the Dpg residue, thereby forming a fully extended (C5) conformation at position 2. The phi and psi values for Met and Phe residues are significantly lower than the values expected for an ideal antiparallel beta conformation causing a twist in the extended backbone both at the N and C termini. Nuclear magnetic resonance studies suggest the presence of a significant population of the peptide molecules in an extended antiparallel beta conformation and the involvement of Dpg NH in a C5 intramolecular hydrogen bond in solutions of deuterated chloroform and deuterated dimethyl sulfoxide. IR studies provide evidence for the presence of an intramolecular hydrogen bond in the molecule and the antiparallel extended conformation in chloroform solution. CD spectra in methanol, trifluoroethanol, and trimethyl phosphate indicate that the Dpg peptide shows slight conformational flexibility, whereas the folded Ac6c analog is quite rigid. The extended Dpg peptide consistently shows the highest activity in human peripheral blood neutrophils, being approximately 8 and 16 times more active than the parent peptide and the folded Ac6c analog, respectively. However, the finding that all four peptides have ED50 (the molar concentration of peptide to induce half-maximal enzyme release) values in the 10(-8)-10(-9) M range suggests that an induced fit mechanism may indeed be important in this ligand-receptor interaction. Moreover, it is also possible that alterations in the backbone conformation at the tripeptide level may not significantly alter the side chain topography and/or the accessibility of key functional groups important for interaction with the receptor.

Amino Acid Sequence↗

PubMed1991

Conformation of cyclic octapeptides. VI. Structure of cyclo-bis-(-L-alanyl-glycyl-L-prolyl-L-phenylalanyl-) tetrahydrate.

C38H48N8O8.4H2O, Mr = 816.9, monoclinic, P21, a = 10.381 (1), b = 13.273 (1), c = 15.742 (1) A. beta = 101.83 (1) degree, V = 2123.1 A3, Z = 2, Dx = 1.278 g cm-3, lambda (Cu K alpha) = 1.5418 A, mu = 7.6 cm-1, F(000) = 872, R = 0.035, wR = 0.045 for 3497 reflections [I greater than 2 sigma (I)], 4552 unique reflections measured. The synthetic cyclic octapeptide crystallizes from water/methanol solution as a tetrahydrate and the crystals are isomorphous to those of the disulfide-bridged cystine analog cyclo-bis(-L-Cys-Gly-L-Pro-L-Phe-) [Kopple, Wang, Cheng & Bhandary (1988). J. Am. Chem. Soc. 110, 4168-4176]. The coordinates of the Cys analog were taken as the starting coordinates for full-matrix least-squares refinement. The cyclic octapeptide ring has two beta turns encompassing the residues Pro-L-Phe, one type I and the other type II, with all peptide links trans. The conformation of the cyclic octapeptide backbone is similar to the Cys analog; all backbone dihedral angles in the two molecules agree to within 6 degrees. This suggests that the disulfide bridge of the Cys analog does not impose any conformational constraint on the octapeptide ring backbone.

Amino Acid Sequence↗

PubMed1991

Conformation of cyclo-bis(-L-valyl-L-proplyl-D-alanyl-), a synthetic cyclic hexapeptide.

C26H42N6O6, Mr = 534.7, monoclinic, C2, a = 20.526 (2), b = 4.923 (1), c = 17.092 (2) A, beta = 126.37 (1) degrees, V = 1390.9 A3, Z = 2, Dm not measured, Dx = 1.28 g cm-3, lambda (Cu K alpha) = 1.5418 A, mu = 7.1 cm-1, F(000) = 576, R = 0.050, wR = 0.049 for 1012 reflections [I greater than 2 sigma (I)], 1501 unique reflections measured at room temperature (296 K). The synthetic cyclic hexapeptide, cyclo-bis(-L-Val-L-Pro-D-Ala-), exhibits exact C2 symmetry in the crystalline state with cis peptide links [omega = -13.1 (7) degrees] between Val and Pro residues; there are no intramolecular hydrogen bonds. The cyclic ring consists of two type VIb cis proline turns fused at the D-Ala residue. The backbone dihedral angles are all in the extended range except for psi Val [72.9 (5) degrees] and phi Pro [-78.9 (5) degrees] on either side of the cis peptide link. The carbonyl O atoms and the amide N atoms in the extended portion of the cyclic peptide form intermolecular hydrogen bonds with another cyclic hexapeptide molecule translated by a cell edge along the crystallographic b axis, forming an infinite stretch of beta-sheets. The parallel beta-sheet structures are separated by about 3.15 A.

Amino Acid Sequence↗

PubMed1991

Crystallization and preliminary X-ray diffraction studies of human salivary alpha-amylase.

Nonglycosylated alpha-amylase, a major component of human parotid saliva, has been crystallized by the vapor diffusion technique using 2-methyl-2,4-pentanediol as the precipitant in the presence of CaCl2 at pH 9.0. The crystals are orthorhombic, space group P2(1)2(1)2(1) with unit cell dimensions of a = 53.3, b = 75.8, and c = 138.1 A. The asymmetric unit contains one amylase molecule. The solvent content is 54%. The crystals are stable to X-rays and diffract up to 2.8 A and appear to be suitable for X-ray diffraction studies.

Crystallization↗

PubMed1990

Structure of a photodimer of 3-acetoxy-2-inden-1-one: 9,10-dioxoindano[2',3':4,3]cyclobuta[1,2-b]indan-4b,4c-diyl diacetate.

C22H16O6, Mr = 376.37, monoclinic, P21/c, a = 9.555 (3), b = 15.664 (2), c = 12.300 (4) A, beta = 100.08 (2) degrees, V = 1812.5 (5) A3, Z = 4, Dx = 1.379 g cm-3, lambda(Cu K alpha) = 1.5418 A, mu = 8.0 cm-1, F(000) = 784, room temperature, R = 0.047, wR = 0.064 for 3203 observed reflections [I greater than 3 sigma (I)]. The molecule exists as the syn-trans isomer in the crystal. The crystal structure exhibits a number of C--H...O intermolecular contacts.

Chemical Phenomena↗

PubMed1990

Structure of delvestine: a norditerpenoid alkaloid from Delphinium vestitum Wall.

C32H46N2O8, Mr = 586.73, m.p. 458-460 K, monoclinic, P2(1), a = 9.187 (2), b = 14.979 (3), c = 11.474 (2) A, beta = 104.09 (2) degrees, V = 1531.5 (9) A3, Z = 2, D chi = 1.27 g cm-3, lambda(Cu K alpha) = 1.5418 A, mu = 7.1 cm-1, F(000) = 632, room temperature, R = 0.039, wR = 0.053 for 3077 observed reflections [I greater than 3 sigma(I)]. The aminoethyl C(21) atom is disordered. There is an intramolecular hydrogen bond between O(1)--H(O1) and N(1) atoms, and between O(3)--H(O3) and O(4), stabilizing the boat conformations adopted by the rings A and D.

Alkaloids↗

PubMed1990

Crystal structure and solution conformation of S,S'-bis(Boc-Cys-Ala-OMe): intramolecular antiparallel beta-sheet conformation of an acyclic cystine peptide.

The conformation of the acyclic biscystine peptide S,S'-bis(Boc-Cys-Ala-OMe) has been studied in the solid state by x-ray diffraction, and in solution by 1H- and 13C-nmr, ir, and CD methods. The peptide molecule has a twofold rotation symmetry and adopts an intramolecular antiparallel beta-sheet structure in the solid state. The two antiparallel extended strands are stabilized by two hydrogen bonds between the Boc CO and Ala NH groups [N...O 2.964 (3) A, O...HN 2.11 (3) A, and NH...O angle 162 (3) degrees]. The disulfide bridge has a right-handed conformation with the torsion angle C beta SSC beta = 95.8 (2) degrees. In solution the presence of a twofold rotation symmetry in the molecule is evident from the 1H- and 13C-nmr spectra. 1H-nmr studies, using solvent and temperature dependencies of NH chemical shifts, paramagnetic radical induced line broadening, and rate of deuterium-hydrogen exchange effects on NH resonances, suggest that Ala NH is solvent shielded and intramolecularly hydrogen bonded in CDCl3 and in (CD3)2SO. Nuclear Overhauser effects observed between Cys C alpha H and Ala NH protons and ir studies provide evidence of the occurrence of antiparallel beta-sheet structure in these solvents. The CD spectra of the peptide in organic solvents are characteristic of those observed for cystine peptides that have been shown to adopt antiparallel beta-sheet structures.

Cystine↗

PubMed1990

Conformation of a cyclic decapeptide analog of a repeat pentapeptide sequence of elastin: cyclo-bis(valyl-prolyl-alanyl-valyl-glycyl).

The conformation of a cyclic decapeptide analog of a repeat sequence of elastin has been determined in the crystalline state using X-ray crystallographic techniques. Tetragonal crystals were grown from a solution of the decapeptide in water; space group P4(2)2(1)2, a = 19.439(2) & c = 13.602(1) A, with four formula units (C40H66N10O10.4H2O) per unit cell. The cyclic decapeptide in the crystal exhibits exact twofold symmetry. The asymmetric unit contains one pentapeptide and two water molecules for a total of 32 nonhydrogen atoms. The structure has been determined by the application of direct methods and refined by full-matrix least squares to an R index of 0.053 for 2272 reflections with intensities greater than 2 sigma(I). The backbone conformation of the asymmetric pentapeptide can be described as consisting of a double beta bend of Type III-I. The Type III turn has Pro (phi = -59.3 degrees, psi = -26.8 degrees) and Ala (phi = -65.9 degrees, psi = -23.1 degrees) at the corners while Type I turn has Ala (phi = -65.9 degrees, psi = -23.1 degrees) and Val (phi = -98.9 degrees, psi = 8.3 degrees) as the corner residues. The cyclic decapeptide has two such double bends linked together by Gly-Val bridges.

Amino Acid Sequence↗

PubMed1989

Structural studies on the biosides of Digitalis lanata: bisdigitoxosides of digitoxigenin, gitoxigenin and digoxigenin.

The crystal structures and conformations of bisdigitoxosides of digitoxigenin (I), gitoxigenin (II) and digoxigenin (III and IV) have been determined using single-crystal X-ray crystallographic techniques. Crystals of (I), (II) and (IV) were grown from ethyl acetate solutions of the glycosides while (III) was grown from a solution of the digitoxoside in ethanol. As in other cardiac glycosides the ring junctions A-B and C-D are cis. The D ring in these structures shows different conformations while the A, B and C rings remain conformationally similar. Although digitoxigenin bisdigitoxoside and gitoxigenin bisdigitoxoside differ from each other in the absence and presence of a hydroxyl group at C(16) of the D ring, these two biosides crystallize in the space group P2(1)2(1)2 [corrected] and are isomorphous. The presence of the hydroxyl group at C(16) does not affect the orientation of the lactone ring and the conformation of the molecule. Digoxigenin bisdigitoxoside crystallizes in two different crystal systems with four molecules of water in the orthorhombic form and one molecule of ethyl acetate in the triclinic form. In both forms the hydroxyl at C(3') of the first sugar forms a hydrogen bond with the ring oxygen of the second sugar. This has also been observed in the trioside digoxin. The torsion angle C(13)-C(17)-C(20)-C(22) in the two forms differs by 7 degrees.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardenolides↗

PubMed1987

Nuclear magnetic resonance spectroscopic and computer-stimulated structural analyses of a heptapeptide sequence found around the N-glycosylation site of a proline-rich glycoprotein from human parotid saliva.

The proline-rich glycoprotein from human parotid saliva has a common heptapeptide sequence around four of six N-glycosylation sites (Maeda, N., H. S. Kim, E. A. Azen, and O. J. Smithies, 1985, J. Biol. Chem., 20:11123-11130). A synthetic model of the heptamer protein sequence, NH2-Q(1)-G(2)-G(3)-N(4)-Q(5)-S(6)-Q(7)-CONH2, was examined by nuclear magnetic resonance (NMR) spectroscopy and the ECEPP/2-VAO4A (Empirical Conformation Energy Program for Peptides) energy minimization computer algorithm (Scheraga, H. A., 1982, Quantum Chemistry Program Exchange, 454; Powell, M. J. D., 1964, Quantum Chemistry Program Exchange, 60). The NMR spectrum was almost completely assigned in dimethylsulfoxide-d6 (DMSO), and the amide chemical shift temperature dependence, phi dihedral angles, and chi 1 rotamer populations elucidated. These data indicated that a significant population of the heptamer could exist as a type I beta-turn [4----1 between Q(5) and G(2)] and/or a type II' beta-turn [4----1 between (Q)5 and G(2) and/or a gamma-turn [3----1 between Q(5) and G(3)] with the amino acid chi 1 torsion angles weighted toward the gauche- conformation. Starting from these three possible conformations, the ECEPP/2-VAO4A rigid geometry energy minimization program was used to find the localized predominant in vacuo structures of this heptapeptide sequence. The type II' beta-turn conformation best fits the data based on internuclear hydrogen-bonding distances, minimum potential energy considerations, and the NMR parameters.

Computer Simulation↗