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1.
Abstract: This review briefly surveys the conformational properties of guest ω‐amino acid residues when incorporated into host α‐peptide sequences. The results presented focus primarily on the use of β‐ and γ‐residues in αω sequences. The insertion of additional methylene groups into peptide backbones enhances the range of accessible conformations, introducing additional torsional variables. A nomenclature system, which permits ready comparisons between α‐peptides and hybrid sequences, is defined. Crystal structure determination of hybrid peptides, which adopt helical and β‐hairpin conformations permits the characterization of backbone conformational parameters for β‐ and γ‐residues inserted into regular α‐polypeptide structures. Substituted β‐ and γ‐residues are more limited in the range of accessible conformation than their unsubstituted counterparts. The achiral β,β‐disubstituted γ‐amino acid, gabapentin, is an example of a stereochemically constrained residue in which the torsion angles about the Cβ–Cγ (θ1) and Cα–Cβ (θ2) bonds are restricted to the gauche conformation. Hybrid sequences permit the design of novel hydrogen bonded rings in peptide structures.  相似文献   

2.
In order to understand the effect of the restrictions posed by the Aib residue on peptide conformation we studied the crystal structure of a dipeptide tBoc-Aib-Phe-OMe. Crystals of this compound are triclinic, space group PI with a= 9.600(1) Å, b=10.262(1) Å, c= 10.799(1) Å, α= 98.43°(1), β=99.18°(1), °=98.87°(1), V= 1021.69(18) Å3 and Z=2. The structure was solved by direct methods and refined to an R-factor of 4.98%. The backbone conformational angles for the Aib residue in molecule A are in the left-handed helical region, while in molecule B they are in the right-handed helical region. The Phe residue in molecule A is in the right-handed helical conformation, while in molecule B it is in the β-region. The peptide units are trans and show significant deviation from planarity [(ω1= 166.67(5)° and ω2=–177.9(5)]. © Munksgaard 1997.  相似文献   

3.
Energy optimizations were performed on some typical conformations of the gastrin C-terminal peptide amide NAc-Trp-Met-Asp-Phe-NH2. Two families of lowest energy conformations were found corresponding to: (a) α-helical structures; (b) conformations having β-structure at the level of Trp residue, and C7-structure at the level of Asp residue. The two aromatic rings were folded on the peptide backbone and ca. 5 Å distant from each other (centre to centre). The last family, favoured by energy and population probability, can better account for conformational experimental results and biological activity observations.  相似文献   

4.
The molecular and crystal structures of one derivative and three model peptides (to the pentapeptide level) of the chiral Cα,α-disubstituted glycine Cα-methyl, Cα-isopropylglycine [(αMe)Val] have been determined by X-ray diffraction. The derivative is mClAc-l -(α Me)Val-OH, and the peptides are Z-l -(αMe)Val-(l -Ala)2-OMe monohydrate, Z-Aib-L-(αMe)Val-(Aib)2-OtBu, and Ac-(Aib)2-l -(αMe)Val-(Aib)2OtBu acetonitrile solvate. The tripeptide adopts a type-I β-turn conformation stabilized by a 1 ← 4N-H . O=C intramolecular H-bond. The tetra- and pentapeptides are folded in regular right-handed 310-helices. All four L-(αMe)Val residues prefer φ, Ψ angles in the right-handed helical region of the conformational map. The results indicate that: (i) the (αMe)Val residue is a strong type-I/III β-turn and helix former, and (ii) the relationship between (αMe)Val chirality and helix screw sense is the same as that of Cα-monosubstituted protein amino-acids. The implications for the use of the (αMe)Val residue in designing conformationally constrained analogues of bioactive peptides are briefly discussed.  相似文献   

5.
Abstract: The conformation of the 19-residue peptaibol chrysospermin C in methanol has been investigated by NMR spectroscopy using selective 15N and 13C labeling of the α-aminoisobutyric acid (Aib) residues. Complete 1H and 13C sequential assignments, including stereospecific assignments for the heavily overlapped resonances from the two Cβ methyl groups of the eight Aib residues, are reported for a peptaibol for the first time. An Aib residue followed by a Pro is an exception to previous suggestions regarding stereospecific assignment of the two Cβ methyl groups of Aib residues. Local nuclear Overhauser effects and 3JHNC and 3JHNCβ scalar couplings indicate that the φ angles of the Aib residues are restricted sterically to local conformations consistent with right-handed helices. Despite these constraints on the eight Aib residues, the NMR data for chrysospermin C in methanol are generally most consistent with an ensemble of transient conformations, including backbone conformations inconsistent with helical structures. Initial NMR measurements for chrysospermin C bound to micelles suggest structural and dynamic differences relative to alamethicin bound to micelles which may be related to differences in gating voltages for formation of ion channels.  相似文献   

6.
NHCH3 (X = Gly 1 , Ala 2 , Aib 3 , Leu 4 and D-Ala 5 ), have been investigated by Raman and circular dichroism (CD) spectroscopy. Solid state Raman spectra are consistent with β-turn conformations in all five peptides. These peptides exhibit similar conformations of the disulfide segment in the solid state with a characteristic disulfide stretching frequency at 519 ± 3 cm-1, indicative of a trans-gauche-gauche arrangement about the Cα—Cβ—S—S—Cβ—Cα bonds. The results correlate well with the solid state conformations determined by X-ray diffraction for peptides 3 and 4. CD studies in chloroform and dimethylsulfoxide establish solvent dependent conformational changes for peptides 1, 3 and 5. Disulfide chirality has been derived using the quadrant rule. CD results together with previously reported nuclear magnetic resonance (n.m.r.) data suggest a conformational coupling between the peptide backbone and the disulfide segment.  相似文献   

7.
The endothelin family of polypeptides are known to exert potent physiological effects which include cardiovascular regulation. The solution conformation and dynamics of c(D-Trp-D-Cys(SO3-Na+)-Pro-D-Val-Leu), a potent endothelin-A receptor-selective antagonist, were characterized in aqueous solution by NMR spectroscopy and molecular modeling. NMR-derived conformational constraints were combined with computer-assisted molecular modeling using distance geometry calculations and energy minimization. The pentapeptide backbone is shown to adopt a single conformation in solution comprising a type II β-turn and an inverse γ-turn, with each residue in the trans conformation. Molecular dynamics were explored using relaxation measurements and low-temperature studies, and indicate that the peptide backbone is highly constrained with little conformational mobility present.  相似文献   

8.
The role exercised by the central residue of the chemotactic N-formyltripeptide HCO-Met-Leu-Phe-OMe (fMLP-OMe) in controlling both the backbone conformation and the biochemical activity is the subject of recent interest. Here, two new centrally constrained fMLP-OMe analogues, namely HCO-Met-azaPro-Phe-OMe ( 4 ) and HCO-Met-(γ-lactam)-Phe-OMe ( 6 ) have been synthesized and their CDCl3 solution conformation and activity have been studied. The azapeptide 4 adopts β-folded conformation with the azaPro residue at the i+2 position and an intramolecular H-bond involving the formylic oxygen and the Phe NH. The γ-lactam tripeptide 6 prefers a semi-extended backbone conformation. When tested on human neutrophils both the new models were found practically devoid of biological activity. The role exerted by the NH groups as well as by the conformational preferences is discussed.  相似文献   

9.
Abstract: Replacement of Phe3 in the endogenous δ‐opioid selective peptide deltorphin I with four optically pure stereoisomers of the topographically constrained, highly hydrophobic novel amino acid β‐isopropylphenylalanine (β‐iPrPhe) produced four pharmacologically different deltorphin I peptidomimetics. Radiolabeled ligand‐binding assays and in vitro biological evaluation indicate that the stereoconfiguration of the iPrPhe residue plays a crucial role in determining the binding affinity, bioactivity and selectivity of [β‐iPrPhe3]deltorphin I analogs: a (2S,3R) configuration of the iPrPhe3 residue in [β‐iPrPhe3]deltorphin I provided the most desirable biological properties with binding affinity (IC50 = 2 n m ), bioassay potency (IC50 = 1.23 n m in MVD assay) and exceptional selectivity for the δ‐opioid receptor over the µ‐opioid receptor (30 000). Further conformational studies based on two‐dimensional NMR and computer‐assisted molecular modeling suggested a model for the possible bioactive conformation in which the Tyr1 and (2S,3R)‐β‐iPrPhe3 residues adopt trans side‐chain conformations, and the linear peptide backbone favors a distorted β‐turn conformation.  相似文献   

10.
The crystal structures of two peptides containing 1-aminocyclohexanecarboxylic acid (Acc6) are described. Boc-Aib-Acc6-NHMe · H2O adopts a β-turn conformation in the solid state, stabilized by an intramolecular 4 → 1 hydrogen bond between the Boc CO and methylamide NH groups. The backbone conformational angles (φAib = – 50.3°, ψAib = – 45.8°; φAcc6 = – 68.4°, ψAcc6 = – 15°) lie in between the values expected for ideal Type I or III β-turns. In Boc-Aib-Acc6-OMe, the Aib residue adopts a partially extended conformation (φAib = – 62.2°, ψAib = 143°) while the Acc6residue maintains a helical conformation (φAcc6 = 48°, ψAcc6= 42.6°). 1H n.m.r. studies in CDCl3 and (CD3)2SO suggest that Boc-Aib-Acc6-NHMe maintains the β-turn conformation in solution.  相似文献   

11.
A new graphic method is described for presenting in two dimensions the φ and ψ dihedral angles that describe the backbone conformation of a peptide or protein chain. For each residue in sequence, φ and ψ are plotted as dots on the y-axis above the next two points on the x-axis representing the residue number. Each dot is linked to the next dot by a slanting line segment (link) and each cis-peptide bond (ω~0°) between residues X and Y is indicated by marking dots ψx and φy with a diamond. This linked φ and ψ chain plot is more useful than an unlinked φ and ψ chain plot for visually recognizing helices, sheets and turns and for graphically comparing several protein structures. Overlaying the linked φ and ψ chain plots for 15 β-hairpins classified as type-I' β-turns revealed that three were significantly different from the rest. The dihedral angles (mean f standard deviation) of the loop residues (L1, L2) for a cluster of 12 β-hairpins with an inverse-common, type-I′β-turn (φL1= 52±7°, ψL1=40±8°, φL2=80±9°, ψL2= -1±13°) are similar to the standard dihedral angles for the type-1′ turn (60, 30, 90 and 0°, respectively).  相似文献   

12.
Deltorphin-I, Tyr-d -Ala-Phe-Asp-Val-Val-Gly-NH2 and dermenkephalin, Tyr-d -Met-Phe-His-Leu-Met-Asp-NH2, two highly related opioid peptides from frog skin, display very similar N-termini but strikingly different C-terminal tails. Nevertheless, both peptides are highly potent at, and exquisitely selective for the δ-opioid receptor. To identify common determinants concuring to the remarkably efficient targeting of deltorphin-I and dermenkephalin, combined use of quantitative two-dimensional nuclear magnetic resonance (53 dipolar interactions studied at four temperatures) and energy calculations using simulated annealing generated five groups of deltorphin-I conformers. These groups were pooled into two families whose overall conformation could be described either by a left-handed helix (Family I) or by a big loop (Family II), both stabilized by H-bonds. Proximity of D-Ala2-Phe3-Asp4 and Val5-Val6-Gly7 triads is an obvious structural similarity between almost all groups in both families of structures. Whereas differences between the two families originated mostly from a transition at Ψ Asp4 backbone dihedral angle, the backbone structures at segment 1–4 are similar and spatial arrangements of Tyr1 (t) and Phe3 (g) are identical in one group of each family. Moreover, these two groups have a N-terminal tetrapeptide whose conformation most closely resembles that of a well-defined group of structures for dermenkephalin. Altogether, these results suggest that conformational attributes that are common to dermenkephalin and deltorphin-I, i.e., the backbone conformation of the N-terminal tetrapeptide and preferential orientations in the side-chain of Tyr1 (t) and Phe3 (g) underlie their ability to bind with high selectivity to the δ-opioid receptor.  相似文献   

13.
The distributions of side-chain conformations in 258 crystal structures of oligopeptides have been analyzed. The sample contains 321 residues having side chains that extend beyond the Cβ atom. Statistically observed preferences of side-chain dihedral angles are summarized and correlated with stereochemical and energetic constraints. The distributions are compared with observed distributions in proteins of known X-ray structures and with computed minimum-energy conformations of amino acid derivatives. The distributions are similar in all three sets of data, and they appear to be governed primarily by intraresidue interactions. In side chains with no β-branching, the most important interactions that determine χ1 are those between the CγH2 group and atoms of the neighboring peptide groups. As a result, the g- conformation (χ1 ? -60°) occurs most frequently for rotation around the Cα-Cβ bond in oligopeptides, followed by the t conformation (χ1 ? 180°), while the g + conformation (χ1 ? 60°) is least favored. In residues with β-branching, steric repulsions between the CγH2 or CγH3 groups and backbone atoms govern the distribution of χ1. The extended (t) conformation is highly favored for rotation around the Cβ-Cγ Cγ-Cδ bonds in unbranched side chains, because the t conformer has a lower energy than the g + g - conformers in hydrocarbon chains. This study of the observed side-chain conformations has led to a refinement of one of the energy parameters used in empirical conformational energy computations.  相似文献   

14.
The crystal and molecular structure of the fully protected dipeptide Boc-Val-(S)-α-MeSer-OMe has been determined by X-ray diffraction techniques. Crystals grown from ethyl acetate/n-pentane mixtures are tetragonal, space group 141, with cell parameters at 295 K of a= 15.307(2), c= 18.937(10)Å, V = 4437.1 Å3, M.W. = 332.40, Z = 8, Dm= 0.99 g/cm3 and Dx= 0.995 g/cm3. The structure was solved by application of direct methods and refined to an R value of 0.028 for 1773 reflections with I≥3σ(I) collected on a CAD-4 diffractometer. Both chiral centers have the (S) configuration. The dipeptide assumes in the solid state an S shape. The urethane moiety is in the cis conformation, while the amide bond is in the common trans conformation. The conformational angles φ1, ψ1 of the Val and φ2, and ψ2 of the (S)-αMeSer fall in the F region of the φ-ψ map. The isopropyl side chain of the Val residue has the (t, g?) conformation, while the Ser side chain has a g+ conformation. The hydrogen bond donor groups are all involved in intermolecular H-bond interactions. Along the quaternary axis the dipeptide molecules are linked to each other with the formation of infinite rows.  相似文献   

15.
The solution structures of DPDPE, a conformationally restricted pentapeptide with the sequence H-Tyr1-d -Pen2-Gly3-Phe4-d -Pen5-OH, and its four β-MePhe4-substituted analogs were examined by a combined approach including the NMR measurements in DMSO and water as well as independent energy calculations. It was concluded that several low energy conformers of DPDPE backbone satisfy the NMR data obtained in this study as well as in previous studies by other authors. These possible solution conformers of DPDPE in both DMSO and water share virtually the same type of cyclic backbone structure, with the Gly3 residue in a conformation close to a γ-turn, and the Phe4 residue in a conformation close to α-helical torsion angles. They differ in the space arrangements of the flexible Tyr1 moiety. The solution structures of the β-MePhe4-substituted analogs of DPDPE are interesting. For analogs with an S-configuration at the Cα atom in the Phe4 residue, the cyclic backbone conformations resemble those of DPDPE itself, whereas for analogs with an R-configuration at the Cα atom, the backbone conformation is somewhat different. This observation is in line with the high biological potencies and selectivities displayed by the former compounds but not by the latter ones. It was noted also that as far as the peptide backbone conformers are concerned, some of the possible DPDPE conformers in water are similar to the previously suggested model for the δ-receptor-bound conformation of DPDPE, becoming virtually identical to this conformation by rotating the side chains of the Tyr1 and the Phe4 residues.  相似文献   

16.
17.
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   

18.
The molecular and crystal structures of the Cα,α-dialkylated α-amino acid residue 1-aminocyclopropane-1-carboxylic acid hemihydrate (H2-Ac3c-O?·½ H2O) and nine derivatives and dipeptides have been determined by X-ray diffraction. The derivatives are pBrBz-Ac3c-OH, Piv-Ac3c-OH, Z-Ac3c-OH, the α- and β-forms of t-Boc-Ac3c-OH, Z-Ac3c-OMe, and the 5(4H)-oxazolone from pBrBz-Ac3c-OH; the dipeptides are H-(Ac3c)2-OMe and c(Ac3c)2. The values determined for the torsion angles about the N-Cα (φ) and Cα-C′ (φ) bonds for the single Ac3c residue of Piv-Ac3c-OH, the α- and β-forms of t-Boc-Ac3-OH and Z-Ac3c-OMe, and the C-terminal Ac3c residue of H-(Ac3c)2-OMe correspond to folded conformations in the “bridge” region of the Ramachandran map. The structures of pBrBz-Ac3c-OH and Z-Ac3c-OH, however, are unusual in having a semi-extended conformation for the φ,ψ angles. The N-terminal Ac3c residue of H-(Ac3c)2-OMe adopts a novel type of C5 conformation, characterized inter alia by an (amino) N ? H-N (peptide) intramolecular hydrogen bond. While the acyl Nα-blocking groups form trans amides (pBrBz-Ac3c-OH and Piv-Ac3c-OH), the urethane groups may adopt either the trans [Z-Ac3c-OH and t-Boc-Ac3c-OH(α-form)] or the cis amide conformations [t-Boc-Ac3c-OH(β-form) and Z-Ac3c-OMe]. The five- and six-membered rings of the 5(4H)-oxazolone and the 2,5-dioxopiperazine, respectively, are planar. The four independent molecules in the asymmetric unit of the free α-amino acid are zwitterionic.  相似文献   

19.
The molecular and crystal structures of the Cα-tetrasubstituted, δ-branched α-amino acid Cα-methyl-homophenylalanine, H-d -(αMe)Hph-OH, and three peptides (to the pentamer level), including the homotripeptide, have been determined by X-ray diffraction. The peptides are Z-l -(αMe)Hph-(l -Ala)2-OMe, pBrBz-[d -(αMe)Hph]3-OtBu and Ac-(Aib)2-l -(αMe)Hph-(Aib)2-OtBu. All the (αMe)Hph residues prefer φ,ψ torsion angles in the helical region of the conformational map. The two terminally blocked tripeptides adopt a β-bend conformation stabilized by a 1→4 C = O?H-N intramolecular H-bond. The terminally blocked pentapeptide is folded in a regular 310-helix. In general, the relationship between (αMe)Hph α-carbon chirality and helix handedness is the same as that exhibited by protein amino acids. A comparison is also made with the conclusions extracted from published work on peptides from other types of Cα-alkylated aromatic α-amino acids. © Munksgaard 1996.  相似文献   

20.
Two-dimensional 1H-NMR methods have been used to obtain complete proton resonance assignments and possible solution conformations of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) and deltorphin-II (H-Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2), naturally occurring μ and §-selective opioids, respectively, in order to examine the conformational characteristics that are closely related to the selectivities towards μ/§ opioid receptors. With the use of the proton-proton distances derived from ROESY measurements in aqueous solution, 50 possible 3D structures are generated by means of distance geometry calculations. The conformers which satisfy the distance constraints and the torsion angles estimated from JNHCxH vicinal coupling constants within the allowable range are then subjected to molecular dynamics simulations for 10 ps after equilibration. Although dermorphin and deltorphin-II are both in equilibrium among many flexible conformers, some conformational differences are observed between these peptides: many conformers of dermorphin show a structure rounded at the N-terminal Tyr-D-Ala-Phe-Gly-Tyr and C-terminal Gly-Tyr-Pro-Ser-NH2 moieties, which are almost at right angles to each other, while those of deltorphin-II are characterized by a ‘hook’ -shaped backbone structure in which the nearly extended conformation of the Val-Val-Gly-NH2 sequence is located under the folded conformation of the N-terminal Tyr-D-Ala-Phe-Glu sequence. The possible relationship between these conformational characteristics and the μ/§-opioid receptor selectivities is discussed.  相似文献   

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