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1.
CD-n.m.r. study of the solution conformation of bradykinin analogs containing α-aminoisobutyric acid
JOHN R. CANN ROBERT E. LONDON CLIFFORD J. UNKEFER RAYMOND J. VAVREK JOHN M. STEWART 《Chemical biology & drug design》1987,29(4):486-496
The conformation in aqueous solution of several α-aminoisobutyric acid (AIB)-containing analogs of bradykinin (BK) has been probed by complementary CD and 1H n.m.r. measurements. The conclusion reached is that substitution of AIB for Pro2 and/or Pro3 in BK stabilizes a degree of β-turn conformation in the N-terminal tetrapeptide moiety of the resulting analogs. Changing the solvent from water to DMSO or TFE further enhances the contribution of particular hydrogen bonded structures to the time-averaged conformation of these peptides. Bradykinin and [AIB7]-BK adopt similar hydrogen bonded conformations in TFE, apparently with a contribution from a β-turn involving their common Arg1-Pro2-Pro3-Gly4 moiety. The contrasting biological activities of BK and its AIB-analogs are considered in terms of the conformational analogy between the AIB-residue and cis1 Pro and the propensity for a β-turn at the N-terminus of the peptide. 相似文献
2.
MAREK CEBRAT MAREK LISOWSKI IGNACY Z. SIEMION MICHAL ZIMECKI ZBIGNIEW WIECZOREK 《Chemical biology & drug design》1997,49(5):415-420
Linear and cyclic analogues of cyclolinopeptide A (CLA) in which one or both phenylalanine residues in fragment Pro6-Pro7-Phe8-Phe9 were substituted by their sulfonated derivatives have been synthesized by SPPS method and cyclization with the BOP reagent. The peptides were examined for their immunosuppressive activity in the humoral and cellular immune response by PFC and DTH tests. All of the analogues retain some immunosuppressive activity of native CLA. Their CD spectra confirm that the optical activity of aromatic residues in CLA depends on their position in the peptide chain. Only the residue in position 8 seems to be optically active. CD spectrum of the cyclic analogue modified in position 9 is very similar to that of native CLA which correlates with its high biological activity. The chiroptical properties of the p-sulfonated Phe-residue are established. © Munksgaard 1997. 相似文献
3.
H. KESSLER A. HAUPT M. SCHUDOK K. ZIEGLER M. FRIMMER 《Chemical biology & drug design》1988,32(3):183-193
Cyclic hexapeptide analogues representing the modified retro sequence of the amino acid residues 7-11 of natural somatostatin are known to protect liver cells from phalloidin poisoning. To determine the influence of steric, lipophilic, and charge effects on (a) the conformation of the backbone and the aromatic side chains and (b) the biological response, the side chains of Phe2, Lys4, and Phe6 of cyclo(-d -Pro1-Phe2-Thr3-Lys(Z)4-Trp5-Phe6-), 1a, one of the most active peptides found so far, were modified by various residues. The discussion of conformationally relevant parameters proves that neither backbone conformations nor populations of aromatic side chain rotamers were altered by these substitutions. The potency of these derivatives in a cytoprotection assay varies by at most one order of magnitude (more or less active than the parent peptide 1a). A qualitative evaluation of lipophilic, steric, and charge effects reveals the dominance of lipophilic effects of aromatic residues; the most potent compounds contain aromatic substructures in the side chain of Lys4. 相似文献
4.
Carmen Mrestani-Klaus Wolfgang Brandt Ralf Schmidt Klaus Neubert Peter W. Schiller 《Archiv der Pharmazie》1996,329(3):133-142
A conformational study of the cyclic β-casomorphin-5 analogues H-Tyr-cyclo[-D-Orn-2-Nal-Pro-Gly-] ( 1 ) (μ-selective agonist; 2-Nal = 2-naphthylalanine), H-Tyr-cyclo[-D-Orn-2-Nal-D-Pro-Gly-] ( 2 ) (mixed μ agonist/δ antagonist) and H-Tyr-cyclo[-D-Orn-Phe-D-Pro-Gly-] ( 3 ) (highly potent μ and δ agonist) has been carried out using 1H NMR spectroscopy. A complete assignment of the proton resonances of the three pentapeptides has been achieved. Compound 1 was shown to exist in two conformations, a major one (90%) characterized by a cis amide bond between 2-Nal3 and Pro4, and a minor one (10%) showing cis amide bonds both between D-Orn2 and 2-Nal3 and between 2-Nal3 and Pro4. Peptides 2 and 3 each showed only one conformer with all-trans peptide bonds in both cases. Temperature dependence studies of the amide proton chemical shifts indicated the existence of several intramolecular hydrogen bonds in the case of compounds 2 and 3 but not in the case of peptide 1. The backbone conformations of 2 and 3 were found to be similar, both being characterized by two consecutive γ turns around the D-Pro4 and D-Orn2 residues, respectively, and by a D-Orn2-CO←HNδ-D-Orn2 hydrogen bond. Altogether, the overall backbone conformation and the preferred side chain conformation were found to be roughly similar for the three title peptides. For all three compounds a close proximity between the aromatic moiety of the 3-position residue (2-Nal or Phe) and the D(or L)-Pro4 residue was established on the basis of ROESY experiments. The examination of low energy conformations obtained in molecular modelling studies by taking into account the various experimentally found NMR parameters (NOEs, vicinal H,H coupling constants, torsion angles, H-bonds) led to proposals of the solution conformation for each peptide. These conformations are in close agreement with a pharmacophore model for μ opioid receptor binding compounds. 相似文献
5.
6.
内啡肽-morphiceptin 的构象和量子力学研究 总被引:1,自引:0,他引:1
本文用分子动力学方法对内啡肽morphiceptin(Tyr1-Pro2-Phe3-Pro4-NH2)进行了构象研究。所得结果与1H,13CNMR和其它实验方法的结果一致,证明我们的构象搜索方法有效。量子力学计算表明此多肽和吗啡在空间和电性上非常相近。因此,它们应作用于同一受体。 相似文献
7.
The cyclopentapeptide, ·L·Val1-L· Pro2-Gly3-L· Val4-Gly5, was synthesized and its conformational characterization was carried out using n.m.r. and theoretical energy calculations. The n.m.r. studies indicated the existence of a cis Val1-Pro2 peptide bond in water and a very strong intramolecular H-bond between the Val1 NH and Gly3 C=O groups. This H-bond forms a β-turn (type II) placing Val4 Gly5 residues within the turn. Two minimum energy conformations were derived, one of which agrees very well with the solution conformation. 相似文献
8.
H. KESSLER H. MATTER G. GEMMECKER H.-J. DIEHL C. ISERNIA S. MRONGA 《Chemical biology & drug design》1994,43(1):47-61
Synthesis and conformational analysis of three cyclic hexapeptides cyclo(-Gly1-Pro2-Phe3-Val4-Xra5-Phe6), Xaa= Phe (I), D-Phe (II) and D-Pro (III), were carried out to examine the influence of proline on the formation of reverse turns and the dynamics of hydrophobic peptide regions. Assignment of all 1H and 13C resonances was achieved by homo- and heteronuclear 2D-NMR techniques (TOCSY, ROESY, HMQC, HMQC-TOCSY and HMBCS-270). The conformational analysis is based on interproton distances derived from ROESY spectra and homo- and heteronuclear coupling constants (E.COSY, HETLOC and HMBCS-270). For structural refinements restrained molecular dynamics (MD) simulations in vacuo and in DMSO were performed. Each peptide exhibits two conformations in DMSO solution due to cis-trans isomerism about the Gly-Pro peptide bond. Surprisingly the cis-Gly-Pro segment in the minor isomers is not involved in a βVI-turn, but forms a turn structure with cis-Gly-Pro in the i and i+ 1 positions. Although no stabilizing hydrogen bond is found in this turn, the φ and ψ-angles closely correspond to a βI-turn [Pro2:φ(i+ 1) -60°, ψ(i+ 1) -30° Phe3: φ(i+ 2) -100°, ψ(i+ 2) -50°]. Hence we call this structural element a pseudo-βI-turn. As expected, in the dominating all-trans isomers proline occupies the i+ 1 position of a standard βI-turn. Therefore, cis-trans isomerization of the Gly1-Pro2 amide bond only induces a local conformational rearrangement, with minor structural changes in other parts of the molecule. However, the geometry of the other regions is affected by the chirality of the i+ 1 amino acid for both isomers (βI for Phe5, βII′ for D-Phe5 or D-Prp5). 相似文献
9.
VINCENT DIVE ATHANASIOS YIOTAKIS CHRISTIAN ROUMESTAND BERNARD GILQUIN JEAN LABADIE FLAVIO TOMA 《Chemical biology & drug design》1992,39(6):506-515
Peptide inhibitors of E. collagenolyticum bacterial collagenase, HS-CH2-CH2-CO-Pro-Yaa (Yaa = Ala, Leu, Nle), have been N-methylated at the Yaa position. The N-methylation slightly increases the inhibitory potency of the modified peptides as compared to the parent compounds. The conformational effects of the N-methylation have been investigated by both 1H 2D-NMR and molecular mechanics energy minimization. Three low-energy conformers have been predicted for the unmethylated parent compounds (Yaa = Ala, Leu, Nle). They are characterized by the Ψ value of the central proline residue: ΨPro= 150c(trans' conformation), Ψpro= 70° (C7 conformation) and ΨPro= -50°(cis' conformation). The N-methylation has been found to strongly increase the energy of the C7 conformer and to a less extent the energy of the cis' conformer. This leaves the trans' conformation as the only low-energy conformer. The ROESY experiments have established that both the N-methyl peptides and the parent compounds adopt the same preferred backbone conformation in water solution, i.e. the trans conformation. Based on these results, the activities of the N-methyl peptides are discussed and a possible conformation of the inhibitor in the bound state is proposed. 相似文献
10.
G. VALLE M. CRISMA C. TONIOLO SUDHANAND R. BALAJI RAO M. SUKUMAR P. BALARAM 《Chemical biology & drug design》1991,38(6):511-518
The crystal structures of four peptides incorporating l-aminocycloheptane-l-carboxylic acid (Ac7c) are described. Boc-Aib-Ac7c-NHMe and Boc-Pro-Ac7c-Ala-OMe adopt β-turn conformations stabilized by an intramolecular 4 × 1 hydrogen bond, the former folding into a type-I/III β-turn and the latter into a type-II β-turn. In the dipeptide esters, Boc-Aib-Ac7c-OMe and Boc-Pro-Ac7c-OMe, the Ac7c and Aib residues adopt helical conformations, while the Pro residue remains semi-extended in both the molecules of Boc-Pro-Ac7c-OMe found in the asymmetric unit. The cycloheptane ring of Ac7c residues adopts a twist-chair conformation in all the peptides studied. 1H-NMR studies in CDCl3 and (CD3)2SO and IR studies in CDCl3, suggest that Boc-Aib-Ac7c-NHMe and Boc-Pro-Ac7c-Ala-OMe maintain the β-turn conformations in solution. 相似文献
11.
Six cyclic retro-analogues of the peptide hormone somatostatin have been synthesized using the solid phase technique. The peptides cyclo(-Xaa1-Phe2-Thr3-Lys4-Ybb5-Phe6-) and cyclo(-Phe1-Xaa2-Thr3-Lys4-Ybb5-Phe6-) with Xaa =d - or l -Pro and Ybb =d - or l -Trp were cyclized via the azide method. The conformations of the cyclic hexapeptides in DMSO-d6 solution were determined by a number of homo- and heteronuclear two-dimensional n.m.r.-techniques including 2D rotating frame NOE-spectroscopy. Two-step coherence transfers, ROE and chemical exchange, are observed for the first time in ROESY spectra. The backbone conformation of the all-trans cyclopeptides consists of a β-turn containing the Pro residue in the position i + 1. These retro-analogues of somatostatin exhibit a high activity in the inhibition of cholate and phalloidin uptake by liver cells (cytoprotective effect); however, the hormonal activities of the natural hormone are completely suppressed. The constitutional and conformational requirements for the cytoprotective activity are discussed. 相似文献
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13.
HORST KESSLER ARMIN GEYER HANS MATTER MATTHIAS KOCK 《Chemical biology & drug design》1992,40(1):25-40
One carbonyl oxygen of the cyclic hexapeptide cycle(-Gly1-Pro2-Phe3-Val4-Phe5-Phe6-) (A) can be selectively exchanged with sulphur using Yokoyama's reagent. Surprisingly it was not the C=O of Gly1 but that of Phe5 which was substituted and cyclo(-Gly1-Pro62-Phe3-Va14-Phe5ψ[CS-NH]Phe6-) (B)was obtained. Thionation results in a conformational change of the peptide backbone although the C=O of Phe5 and the corresponding C=S are not involved in internal hydrogen bonds. Two isomers in slow exchange, containing a CIS Gly1-Pro2 bond in a βVIa-turn (minor) and a trans Gly-Pro bond in a βII′-turn (major), were analyzed by restrained molecular dynamics in vacuo and in DMSO as well as using time dependent distance constraints. It is impossible to fit all experimental data to a static structure of each isomer. Interpreting the conflicting NOES, local segment flexibility is found. MD simulations lead to a dynamic model for each structure with evidence of an equilibrium between a βI- and βII-turn about the Val4-Phe5 amide bond in both the cis and trans isomers. Additionally proton relaxation rates in the rotating frame (R1p) were measured to verify the assumption of this fast βI/βII equilibrium within each isomer. Significant contributions to R1p-rates from intramolecular motions were found for both isomers. Therefore it is possible to distinguish between at least four conformers interconverting on different time scales based on NMR data and MD refinement. This work shows that thionation is a useful modification of peptides for conformation-activity investigations. 相似文献
14.
Stereochemical constraints have been introduced into the enkephalin backbone by substituting α-aminoisobutyryl (Aib) residues at positions 2 and 3, instead of Gly. 1H n.m.r. studies of Tyr-Aib-Gly-Phe-Met-NH2, Tyr-Aib-Aib-Phe-Met-NH2 and Tyr-Gly-Aib-Phe-Met-NH2 demonstrate the occurrence of folded, intramolecularly hydrogen bonded structures in organic solvents. Similar conformations are also favoured in the corresponding t-butyloxycarbonyl protected tetrapeptides, which lack the Tyr residue. A β-turn centred at positions 2 and 3 is proposed for the Aib2-Gly3analog. In the Gly2-Aib3analog, the β-turn has Aib3-Phe4as the corner residues. The Aib2-Aib3analog adopts a consecutive β-turn or 310 helical conformation. High in vivo biological activity is observed for the Aib2and Aib2-Aib3analogs, while the Aib3peptide is significantly less active. 相似文献
15.
The structure of cyclic antagonists of luteinizing hormone-releasing hormone (LHRH), Ac-D-Phe(p-Cl)1-D-Phe(p-C1)2-Trp3-Ser4-c(Asp5-D-Arg6-Leu7-Lys8)-Pro9-D-Ala10-NH2 ( I ), Ac-D-Phe(p-Cl)l-D-Phe(p-Cl)2-D-Trp3-Ser4-c(Glu5-Arg6-Leu7-Lys8)-Pro9-D-Ala10-NH2 ( II ) and their linear analogues, Ac-D-Phe(p-Cl)1-Phe(p-C1)2-Trp3-Ser4-Asp5-D-Arg6-Leu7-Lys8-Pro9-D-Ala10-NH2 ( III ) and Ac-D-Phe(p-Cl)1-D-Phe(p-C1)2-Trp3-Ser4-Glu5-D-Arg6-Leu7-Lys8-Pro9-D-Ala10-NH2 ( IV ), have been studied by NMR spectroscopy. The cyclic peptides I and II are more potent antagonists than the corresponding linear peptides in an in vivo assay. All the peptides show propensity of an unusual type II′β-turn involving residues 3–6. Cyclic analogues also show some additional structure around residues 7 and 8 which is absent in the linear peptides. This additional structure in the cyclic peptides may be due to a minor conformation with a β-turn between residues 5 and 8. © Munksgaurd 1995. 相似文献
16.
JOHN R. CANN ROBERT E. LONDON JOHN M. STEWART NICHOLAS A. MATWIYOFF 《Chemical biology & drug design》1979,14(5):388-392
Analysis of the effect of temperature on the circular dichroism spectrum of bradykinin has led to a more precise understanding of the solution conformation of the peptide. Circular dichroism and 13C n.m.r. have been used in a complementary fashion to support the picture that bradykinin spends a maximum of about 20% of its time in a partially ordered conformation featuring a γ-turn with Pro7 as the second residue. Since the γ-turn probability is insensitive to temperature, some other conformational effect dominated by the structure of water presumably produces the pronounced change in the circular dichroism spectrum with increasing temperature. 相似文献
17.
SHAW-LIN HAN EVELYN R. STIMSON FREDERICK R. MAXFIELD HAROLD A. SCHERAGA 《Chemical biology & drug design》1981,17(3):297-315
A conformational study has been carried out on a series of linear proline-containing oligopeptides (ZGP, ZGPL, ZGPLG and ZGPLGP) in both the crystalline state and in DMSO-d6, solution, using Raman and n.m.r. spectroscopy. The amide I and HI bands in the Raman spectra of the crystalline forms indicate the presence of a type I β-bend conformation in ZGPLG and ZGPLGP, but not in ZGP and ZGPL. This result is in agreement with X-ray data on these mole cules. The Raman spectra of these peptides in solution indicate that more than one conformation is present, i.e. that the β-bend structure of the solid form of ZGPLG and ZGPLGP is destabilized by DMSO-d6. 13C and 1H n.m.r. data also demonstrate the presence of more than one conformation in ZGP, ZGPL, ZGPLG and ZGPLGP in DMSO-d6 solution. These isomers differ in their con formation (cis and trans) about their Gly-Pro peptide bonds and possibly about the Cα-C' bond of the C-terminal proline in ZGPLGP. For ZGP, ZGPL, ZGPLG and ZGPLGP, the ensemble of conformations in DMSO-d6 includes C5 and C7 hydrogen-bonded rings; in addition, ZGPLGP may contain a small percentage of a β-bend conformation (at Pro2-Leuj3) with trans peptides in both Gly-Pro moieties. 相似文献
18.
Synthesis and conformational analysis of the S-glycosylated cyclic hexapeptide cyclo(-d -Pro1-Phe2-Cys3(tetra-O-acetyl-β-d -galactopyranosyl)-Trp4-Lys(Z)5-Phe6-) I was carried out to examine the influence of a saccharide residue in position i of a standard β-turn on the formation of reverse turns and on the biological activity. Synthesis was carried out in the liquid phase employing a galactosylated cysteine building block. The cyclization reagents DPPA/NaHCO3 avoided high dilution conditions. Spectroscopic data were extracted from homo- and heteronuclear 2D-NMR techniques (TOCSY, NOESY, HMQC, HMQC-TOCSY, HMBCS-270). For structural refinement restrained molecular dynamics (MD) simulations in vacuo and with explicit DMSO as solvent were performed. Finally, simulations in DMSO without experimental restraints provided insight in stability and dynamics of the structural model. A comparison of the S-glycosylated Cys3 peptide with the analogous Thr3 peptide exhibits a similar overall conformation of the hexapeptide [βII’d -Pro-Phe and another β-turn about Trp4-Lys5(Z)]. However, the latter shows a distinct dynamic flip βI, βII in the glycopeptide, whereas the Thr-analogue only populates βI. This influence is attributed to a βI stabilizing effect of a hydrogen bridge of Thr-O, in position i to the NH of the amino acid in position i+ 2, which is lacking in the glycosylated compound. 相似文献
19.
MARK D. SHENDEROVICH GREGORY V. NIKIFOROVICH ALEXANDER A. GOLBRAIKH 《Chemical biology & drug design》1991,37(4):241-251
Theoretical conformational analysis was carried out for several tetrapeptide analogues of β-casomorphin and dermorphin containing a Phe residue in position 3. Sets of low-energy backbone structures of the μ-selective peptides [N-Me-Phe3, d -Pro4]-morphiceptin and Tyr-d -Orn-Phe-Asp-NH2 were obtained. These sets of structures were compared for geometrical similarity between themselves and with the low-energy conformations found for the δ-selective peptide Tyr-d -Cys-Phe-d -Pen-OH and nonactive peptide Tyr-Orn-Phe-Asp-NH2. Two pairs of geometrically similar conformations of μ-selective peptides, sharing no similarity with the conformations of peptides showing low affinity to the μ-receptor, were selected as two alternative models of probable μ-receptor-bound backbone conformations. Both models share geometrical similarity with the low-energy structures of the linear μ-selective peptide Tyr-d -Ala-Phe-Phe-NH2. Putative binding conformations of Tyr1 and Phe3 side chains are also discussed. 相似文献
20.
MITSUAKI NARITA NORIHIRO OHKAWA SATOSHI NAGASAWA SHIZUKO ISOKAWA 《Chemical biology & drug design》1984,24(2):129-134
The conformational properties of Boc-Leu3-(Pro2GlyLeu3)n-Pro2Gly-OH(n = 0, 1, 3, and 5) and Boc-Leu3-(Pro2GlyLeu3)n-Pro2Gly-OBzl (n = 7, 9, and 11) were investigated in various organic solvents of high polarity using molar rotation and CD measurements. The peptides examined are assembled by the N-terminal, internal, and C-terminal segments having the sequences of Boc-Leu3, Pro2Gly-Leu3, and Pro2Gly-OX (X = H or Bzl), respectively. The conformational studies using the molar rotation of the oligopeptides and polypeptides in MeOH, DMSO, DMF, DMA, and NMP have made it clear that all the peptides have a randomly coiled structure. CD spectral patterns of the peptides in MeOH were essentially the same as each other and indicative of the randomly coiled structure. The additive nature of the total molar rotation and total molar ellipticity in Boc-Leu3-(Pro2GlyLeu3)n-Pro2Gly-OX (X = H or Bzl) indicates that the “peptide segment separation” is indeed in operation in organic solvents of high polarity and that the peptide molecule can be considered to be assembled with the small peptide segments having a randomly coiled structure. 相似文献