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1.
6-Hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (6Htc) has been proposed as a rigid mimic of tyrosine conformation in opioid ligand-receptor complex. The significant receptor binding to mu and delta opioid receptors of respective analogues of deltorphin, dermorphin, and endomorphin with D,L-6Htc prove initial prediction.  相似文献   

2.
β‐Amino acids containing hybrid peptides and β‐peptides show great potential as peptidomimetics. In this paper we describe the synthesis and affinity toward the µ‐ and δ‐opioid receptors of β‐peptides, analogues of Leu‐enkephalin, deltorphin I, dermorphin and α,β‐hybrides, analogues of deltorphin I. Substitution of α‐amino acid residues with β3homo‐amino acid residues, in general resulted in decrease of affinity to opioid receptors. However, the incorporation β3h‐D ‐Ala in position 2 or β3hPhe in position 3 of deltorphin I resulted in potent and selective ligand for δ‐opioid receptor. The NMR studies of β‐deltorphin I analogue suggest that conformational motions in the central part of the peptide backbone are partially restricted and some conformational preferences can be expected. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

3.
We have previously proposed a model for the δ-opioid receptor binding conformation of the high affinity tetrapeptide Tyr-c[D -Cys-Phe-D -Pen] OH (JOM-13) based on experimental and theoretical conformational analysis of this peptide and a correlation of conformational preferences of further conformationally restricted analogues of this tetrapeptide with their receptor binding affinities. A key element of this model is the requirement that the Phe3 side chain exist in the x1 = −60° conformation. Conformational calculations on the residue 3 dehydrophenylalanine analogues of JOM-13 suggest that while the dehydro(Z) phenylalanine analogue can be superimposed easily with the proposed binding conformer of JOM-13, the dehydro(E)phenylalanine analogue cannot. These results lead to the prediction that the dehydro(Z)-phenylalanine analogue should display similar δ-receptor binding affinity as JOM-13 while the dehydro(E)phenylalanine analogue is expected to bind less avidly. Synthesis and subsequent opioid receptor binding analysis of the dehydrophenylalanine analogues of JOM-13 confirm these predictions, lending support to the δ-pharmacophore model. © 1996 John Wiley & Sons, Inc.  相似文献   

4.
Conformationally and configurationally restricted rotameric probes of phenylalanine have been incorporated in the sequence of substance P (SP)—Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2—for analyzing the binding pockets of Phe7 (S7) and Phe8 (S8), in the neurokinin-1 receptor. These analogues of phenylalanine are (2S, 3R)- and (2S, 3S)-indanylglycines, E- and Z-α, β-dehydrophenylalanines, and 2(S)-α, β-cyclopropylphenylalanines [ΔE Phe, ΔZPhe, ▿E2(S)Phe, and ▿Z2(S)Phe]. Binding data obtained with either conformationally (Ing diastereoisomers) or configurationally (ΔEPhe, ΔZPhe) probes have unveiled large differences in the binding potencies of these rotameric probes. With the support of nmr data and energy calculations done on these SP-substituted analogues, we attempt to answer questions inherent to such study. First, none of these six probes prevents the formation of bioactive conformation(s) of the backbone of SP. Second, both diastereoisomers (S, S) and (S, R) of indanylglycine preferentially adopt, in the sequence of SP, the gauche (−) and trans side-chain orientations, respectively, as previously postulated from energy calculations with model peptides. However, in solution, the difference in energy between these rotamers included in the sequence of SP, compared to model peptides, is smaller since the other rotamer can be detected in [(2S, 3R) Ing7]SP. Finally, from this study we can hypothesize that the large variations observed in the affinities of Phe7 substituted analogues of SP must come from steric hindrance in the S7 binding site, which drastically restricts the space filling around the Cα (SINGLE BOND) Cβ bond of residue 7. © 1996 John Wiley & Sons, Inc.  相似文献   

5.
A molecular mechanics study (grid search and energy minimization) of the highly δ receptor-selective δ opioid antagonist H-Tyr-Tic-Phe-OH (TIP; Tic: tetrahydroisoquinoline-3-car-boxylic acid) resulted in four low energy conformers with energies within 2 kcal/mol of that of the lowest energy structure. These four conformers contain trans peptide bonds only and represent compact structures showing various patterns of aromatic ring stacking. The centrally located Tic residue imposes several conformational constraints on the N-terminal dipeptide segment; however, the results of molecular dynamics simulations indicated that this tripeptide still shows some structural flexibility, particularly at the Phe3 residue. Analogous studies performed with the structurally related μ receptor-selective μ agonist H-Tyr-D -Tic-Phe-NH2 resulted in low energy structures that were also compact but showed patterns of ring stacking different from those obtained with TIP. Superim-position of low energy conformers of TIP and H-Tyr-D -Tic-Phe-NH2 revealed that the Phe3 residues of the L -Tic- and the D -Tic peptide were always located on opposite sides of the plane defined by the Tic residue, thus providing an explanation for the distinct activity profiles of the two compounds in structural terms. Attempts to demonstrate spatial overlap between the pharmacophoric moieties of low energy conformers of TIP and the nonpeptide δ antagonist naltrindole were made by superimposing either the Tyr1 and Tic2 aromatic rings and the N-terminal amino group or the Tyr1 and Phe3 aromatic rings and the N-terminal amino group of the peptide with the corresponding aromatic rings and nitrogen atom in the alkaloid structure. In each case a low energy structure of TIP was found that showed good spatial overlap of all three specified pharmacophoric groups. These two conformers may represent candidate structures for the δ receptor-bound conformation of TIP. © 1994 John Wiley & Sons, Inc.  相似文献   

6.
Syntheses are described of new dermorphin and [D-Ala2]deltorphin I analogues in which the phenylalanine, the tyrosine or the valine residues have been substituted by the corresponding N-alkylglycine residues. Structural investigations by CD measurements in different solvents and preliminary pharmacological experiments were carried out on the resulting peptide-peptoid hybrids. The contribution from aromatic side chain residues is prominent in the CD spectra of dermorphin analogues and the assignment of a prevailing secondary structure could be questionable. In the CD spectra of deltorphin analogues the aromatic contribution is lower and the dichroic curves indicate the predominance of random conformer populations. The disappearance of the aromatic contribution in the [Ntyr1,D-Ala2]-deltorphin spectrum could be explained in terms of high conformational freedom of the N-terminal residue. The kinetics of degradation of the synthetic peptoids digestion by rat and human plasma enzymes were compared with that of [Leu5]-enkephalin. The binding to opioid receptors was tested on crude membrane preparations from CHO cells stably transfected with the mu- and delta-opioid receptors. The biological potency of peptoids was compared with that of dermorphin in GPI preparations and with that of deltorphin I in MVD preparations. All the substitutions produced a dramatic decrease in the affinity of the peptide-peptoid hybrids for both the mu- and delta-opioid receptors. Nval5 and/or Nval6 containing hybrids behaved as mu-opioid receptor agonists and elicit a dose-dependent analgesia (tail-flick test) when injected i.c.v. in rats.  相似文献   

7.
Studies on the conformation of several structural analogues of norephedrine, thiophene, carbazole and furan, were carried out using the differential PCILO method. The erythro-forms of these compounds possess minima on the conformation map corresponding to a gauche conformation with synclinal H-atoms. This result is in good agreement with the proton-proton coupling constants found in previous NMR-studies. 1H-NMR-studies suggest for the threo-isomers of the studied molecules an equilibrium between the trans- and gache-conformations of the ethanolamine chain. Present calculations agree fairly well with this result. All the studied molecules possess conformational minima corresponding to the folded form of the side chain believed responsible for the physiological activity of norephedrine. The distances between ‘N’ and ‘O’ atoms in this preferred conformation correspond to the model proposed by Kier and Pullman for α-adrenergic receptors.  相似文献   

8.
Abstract: Two series of serotonin analogues, in which the side chain amino group is constrained in the gauche or trans conformation, were utilized to study the preferred conformation of serotonin for interaction with two different neuronal sites. 6-Hydroxytetrahydro-β-carboline and 6-hydroxy-3-aminotetrahydrocarbazole were found to be potent inhibitors of serotonin uptake into hypothalamic synaptosomes, with IC50 values of 0.13 μM for each analogue. The type of inhibition, as determined by Dixon plots, was found to be competitive, with Ki's of 3.0 × 10−8 M and 4.6 × 10−8 M for the β-carboline and carbazole derivatives, respectively. Methoxylation or lack of a hydroxy group at the 6 position of the carbazole derivative did not alter inhibitory potency, while methoxy or benzyloxy substitution decreased potency 22- to 326-fold. The serotonin analogues were 20 to 30 times less potent in inhibiting the synaptosomal transport of the catecholamines. With regard to [3H]serotonin binding to membranes obtained from brain homogenates, both analogues exhibited poor affinity compared with the transmitter. However, the β-carboline derivative was three times as potent as the carbazole analogue. These findings and earlier ones with regard to the effect of the serotonin analogues on brain monoamine oxidase activity support the idea that serotonin analogues interact differentially with the three different serotonergic sites examined.  相似文献   

9.
We describe the solution (1H-nmr) and calculated conformations of the opiatelike peptide dermorphin and the analysis of structure–conformation–activity relationships in the series [Alan]-dermorphin. We used 1H-nmr spectroscopy to study dermorphin and its analogs [Alan]-dermorphin (with n = 1, 2…7) dissolved in dimethylsufoxide. Conformational energy calculations using semiempirical partitioned energy function methods were then carried out on dermorphin and its [L -Ala2]-analog. Agreement between calculation and experiment is satisfying, both suggesting predominance of a type I β-turn around Pro6-Ser7 at the C-terminus and of an extended structure in the central sequence Phe3-Gly4-Tyr5. Detailed analysis by step-by-step substitutions with Ala indicates that intraresidue interactions dominate over medium-range interactions (between adjacent residues), although the latter may also have a noticeable influence in shaping conformations. As a general feature, the effects of substitutions on the arrangement of side chains are always larger on the succeeding residue than on the preceding residue. Almost all the variations of activity observed in the analogs can be explained from conformational changes occurring in the aromatic side chains of the biologically important Tyr1, Phe3, and Tyr5 on substitutions effected on adjacent residues (fluctuations via medium-range interactions).  相似文献   

10.
The functions of two conserved residues, Phe135 and Pro136, located at the apex of the Cys loop of the nicotinic acetylcholine receptor are investigated. Both residues were substituted with natural and unnatural amino acids, focusing on the role of aromaticity at Phe135, backbone conformation at Pro136, side chain polarity and volume, and the specific interaction between the aromatic side chain and the proline. NMR spectroscopy studies of model peptides containing proline and unnatural proline analogues following a Phe show a consistent increase in the population of the cis conformer relative to peptides lacking the Phe. In the receptor, a strong interaction between the Phe and Pro residues is evident, as is a strong preference for aromaticity and hydrophobicity at the Phe site. A similar influence of hydrophobicity is observed at the proline site. In addition, across a simple homologous series of proline analogues, the results reveal a correlation between receptor function and cis bias at the proline backbone. This could suggest a significant role for the cis proline conformer at this site in receptor function.  相似文献   

11.
Schmidt, R., D. Menard, C. Mrestani-Klaus, N. N. Chung, C. Lemieux and P. W. Schiller. Structural modifications of the N-terminal tetrapeptide segment of [d-Ala2]deltorphin I: effects on opioid receptor affinities and activities in vitro and on antinociceptive potency. Peptides 18(10) 1615–1621, 1997.—A series of deltorphin I analogs containing d- or l-N-methylalanine (MeAla), d- or l-proline (Pro), α-aminoisobutyric acid (Aib), sarcosine (Sar) or D-tert-leucine (Tle) in place of d-Ala2, or phenylalanine in place of Tyr1, was synthesized. The opioid activity profiles of these peptides were determined in μ and δ opioid receptor-representative binding assays and bioassays in vitro as well as in the rat tail flick test in vivo. In comparison with the deltorphin I parent, both the l- and the d-MeAla2-analog were slightly more potent δ agonists in the mouse vas deferens (MDV) assay, and the d-MeAla2-analog showed two-fold higher antinociceptive potency in the analgesic test. In view of the fact that deltorphin analogs with an unsubstituted l-amino acid residue in the 2-position generally lack opioid activity, the observed high δ opioid potency of [l-MeAla2]deltorphin I is postulated to be due to the demonstrated presence of a conformer with a cis Tyr1-MeAla2 peptide bond, since the cis conformer allows for a spatial arrangement of the pharmacophoric moieties in the N-terminal tripeptide segment similar to that in active deltorphin analogs containing a d-amino acid residue in the 2-position. Substitution of Aib in the 2-position led to a compound, H-Tyr-Aib-Phe-Asp-Val-Val-Gly-NH2, which displayed lower δ receptor affinity than the parent peptide but higher δ selectivity and, surprisingly, three times higher antinociceptive potency. The d- and l- Pro2-, Sar2- and d-Tle2-analogs showed much reduced δ receptor affinities and were inactive in the tail flick test. Replacement of Tyr1 in deltorphin I with Phe produced a 32-fold decrease in δ receptor affinity but only a 7-fold drop in antinociceptive potency.  相似文献   

12.
The sequence of deltorphin I, a δ-selective opioid agonist, has been systematically modified by inserting conformationally constrained Cα,α disubstituted apolar residues in the third position. As expected, substitution of Phe with Ac6c, Ac5c and Ac3c yields analogues with decreasing but sizeable affinity. Surprisingly, substitution with Aib yields an analogue with almost the same binding affinity of the parent compound but with a greatly increased selectivity. This is the first case of a potent and very selective opioid peptide containing a single aromatic residue in the message domain, that is, only Tyr1. Here we report a detailed conformational analysis of [Aib3]deltorphin I and [Ac6c3]deltorphin I in DMSO at room temperature and in a DMSO/water cryomixture at low temperature, based on NMR spectroscopy and energy calculations. The peptides are highly structured in both solvents, as indicated by the exceptional finding of a nearly zero temperature coefficient of Val5 NH resonance. NMR data cannot be explained on the basis of a single structure but it was possible to interpret all NMR data on the basis of a few structural families. The conformational averaging was analysed by means of an original computer program that yields qualitative and quantitative composition of the mixture. Comparison of the preferred solution conformations with two rigid δ-selective agonists shows that the shapes of [Aib3]deltorphin I and [Ac6c3]deltorphin I are consistent with those of rigid agonists and that the message domain of opioid peptides can be defined only in conformational terms.  相似文献   

13.
C‐2 dimethylated/unmethylated thiazolidine‐4‐carboxylic acid and C‐2 dimethylated oxazolidine‐4‐carboxylic acid were introduced into the insect kinin core pentapeptide in place of Pro3, yielding three new analogues. NMR analysis revealed that the peptide bond of Phe2‐pseudoproline (ΨPro)3 is practically 100% in cis conformation in the case of dimethylated pseudoproline‐containing analogues, about 50% cis for the thiazolidine‐4‐carboxylic acid analogue and about 33% cis for the parent Pro3 peptide. The diuretic activities are consistent with the population of cis conformation of the Phe2‐ΨPro3/Pro3 peptide bonds, and the results confirm a cis Phe‐Pro bond as bioactive conformation. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

14.
Three Tic-containing (Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) model peptides were synthesized to assess the tendency of this constrained Phe analogue to fold into a beta-bend and a helical structure, and to adopt a preferred side-chain disposition. The results of the solution conformational analysis, performed by using Fourier transform infrared absorption and 1H nuclear magnetic resonance, indicate that in chloroform the -Aib-D-Tic-Aib-, -(Aib)2-D-Tic-(Aib)2-, and -L-Pro-D-Tic- sequences fold into intramolecularly H-bonded forms to a great extent. An X-ray diffraction analysis on p-BrBz-(Aib)2-DL-Tic-(Aib)2-OMe monohydrate and p-BrBz-L-Pro-D-Tic-NHMe allows us to conclude that, while the pentapeptide methylester forms an incipient (distorted) 3(10)-helix, the dipeptide methylamide adopts a type-II beta-bend conformation. In both cases, the D-Tic side-chain conformation is D, gauche(-). The implications for the use of the Tic residue in designing conformationally restricted analogues of bioactive peptides are briefly discussed.  相似文献   

15.
The stereochemical requirements for δ-opioid receptor binding of a series of linear peptide antagonists with a novel conformationally restricted Phe analogue (Tic) as a second residue were examined by using a variety of computational chemistry methods. The δ-opioid receptor analogues with significant affinity, Tyr-Tic-NH2 (TI-NH2), Tyr-Tic-Phe-OH (TIP), Tyr-Tic-Phe-NH2(TIP-NH2), Tyr-Tic-Phe-Phe-OH (TIPP), Tyr-Tic-Phe-Phe-NH2) (TIPP-NH2), and the low affinity δ-opioid peptides Tyr-Pro-Phe-Pro-NH2 (morphiceptin) and Tyr-Phe-Phe-Phe-NH2 (TPPP-NH2), were included in this study. The conformational profiles of these peptides were obtained by consecutive cycles of high and low temperature molecular dynamic simulations, coupled to molecular mechanical energy minimization carried out until no new conformational minima were obtained. Comparing the results for TPPP-NH2 and TIPP-NH2, the presence of the conformationally restricted Tic residue did not greatly reduce the number of unique low energy conformations, but did allow low energy conformers involving cis bonds between the first two residues. The conformational libraries of these peptides were examined for their ability to satisfy the three key ligand components for receptor recognition already identified by previous studies of high affinity cyclic (Tyr1-D -Pen2-Gly3-Phe4-D -Pen5) enkephalin (DPDPE) type agonists: a protonated amine group, an aromatic ring, and a lipophilic moiety in a specific geometric arrangement. Two types of conformations common to the five high δ-opioid affinity L -Tic analogues were found that satisfied these requirements, one with a cis and the other with a trans peptide bond between the Tyr1 and Tic2 residues. Moreover, both the Tic2 and Phe3 residues could mimic the hydrophobic interactions with the receptor of the Phe4 moiety in the cyclic DPDPE type agonists, consistent with the appreciable affinity of both di-and tripeptides. The low δ-opioid receptor affinity of morphiceptin can be understood as the result of conformational preferences that prevent the fulfillment of this pharmacophore for recognition. © 1996 John Wiley & Sons, Inc.  相似文献   

16.
The synthesis of new dermorphin analogues is described. The (R)‐alanine or phenylalanine residues of natural dermorphin were substituted by the corresponding α‐methyl‐β‐azidoalanine or α‐benzyl‐β‐azido(1‐piperidinyl)alanine residues. The potency and selectivity of the new analogues were evaluated by a competitive receptor binding assay in rat brain using [3H]DAMGO (a μ ligand) and [3H]DELT (a δ ligand). The most active analogue in this series, Tyr‐(R)‐Ala‐(R)‐α‐benzyl‐β‐azidoAla‐Gly‐Tyr‐Pro‐Ser‐NH2 and its epimer were analysed by 1H and 13C NMR spectroscopy and restrained molecular dynamics simulations. The dominant conformation of the investigated peptides depended on the absolute configuration around Cα in the α‐benzyl‐β‐azidoAla residue in position 3. The (R) configuration led to the formation of a type I β‐turn, whilst switching to the (S) configuration gave rise to an inverse β‐turn of type I′, followed by the formation of a very short β‐sheet. The selectivity of Tyr‐(R)‐Ala‐(R) and (S)‐α‐benzyl‐β‐azidoAla‐Gly‐Tyr‐Pro‐Ser‐NH2 was shown to be very similar; nevertheless, the two analogues exhibited different conformational preferences. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.  相似文献   

17.
A theoretical conformational analysis (molecular mechanics study) of nine cyclic tetrapeptides, structurally related to the highly mu-receptor-selective dermorphin analogue H-Tyr-D-Orn-Phe-Asp-NH2, was performed. These compounds display considerable diversity in their mu-receptor affinity and selectivity. A systematic search and subsequent energy minimization in absence of the exocyclic Tyr1 residue and Phe3 side chain revealed the constrained nature of the 11-13-membered ring structures contained in these analogues. No more than four low-energy conformers (within 2 kcal/mol of the lowest energy conformation) were found in each case. After attachment of the Tyr1 moiety and Phe3 side chain to the "bare" low-energy ring structures, a systematic search and energy minimization of these exocyclic moieties resulted in a limited number of low-energy conformational families for all compounds. Five analogues with high mu-receptor affinity--H-Tyr-D-Orn-Phe-Asp-NH2, H-Tyr-D-Orn-Phe-D-Asp-NH2, H-Tyr-D-Asp-Phe-Orn-NH2, H-Tyr-D-Asp-Phe-A2bu-NH2 (A2 bu: alpha, gamma-diaminobutyric acid) and H-Tyr-D-Cys-Phe-Cys-NH2--all showed a tilted stacking interaction between the Tyr1 and Phe3 aromatic rings in the lowest or second lowest energy conformation found. The same kind of stacking was not possible in low-energy conformers of the four analogues with poor affinity for the mu-receptor [H-Tyr-L-Orn-Phe-Asp-NH2, H-Tyr-D-Orn-D-Phe-Asp-NH2, H-Tyr-D-Orn-Phe(NMe)-Asp-NH2 [Phe(NMe): N alpha-methylphenylalanine], and H-Tyr-D-Orn-Phg-Asp-NH2 (Phg: phenylglycine)].(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

18.
Fourteen monocyclic analogues of trypsin inhibitor SFTI-1 isolated from sunflower seeds were synthesized by the solid-phase method. The purpose of this work was to establish the role of a disulfide bridge present in inhibitor’s side chains of Cys3 and Cys11 in association with serine proteinases. This cyclic fragment was replaced by the disulfide bridges formed by l-pencillamine (Pen), homo-l-cysteine (Hcy), N-sulfanylethylglycine (Nhcy) or combination of the three with Cys. As in the substrate specificity the P1 position of the synthesized analogues Lys, Nlys [N-(4-aminobutyl)glycine], Phe or Nphe (N-benzylglycine) were present, and they were checked for trypsin and chymotrypsin inhibitory activity. The results clearly indicated that Pen and Nhcy were not acceptable at the position 3, yielding inactive analogues, whereas another residue (Cys11) could be substituted without any significant impact on the affinity towards proteinase. On the other hand, elongation of the Cys3 side chain by introduction of Hcy did not affect inhibitory activity, and an analogue with the Hcy–Hcy disulfide bridge was more than twice as effective as the reference compound ([Phe5] SFTI-1) in inhibition of bovine α-chymotrypsin.  相似文献   

19.
As a continuation of our program to study structure-activity relationships of opiate peptides, we report the syntheses and biological activities of a series of 14-membered cyclic dermorphin analogues closely related to enkephalin analogue Tyr-c[D-A2bu-Gly-Phe-Leu] incorporating a phenylalanine at the third position in place of glycine. In addition to two parent dermorphin analogues Tyr-c[D-A2bu-Phe-Phe-(L and D)-Leu], four stereoisomeric retro-inverso modified analogues Tyr-c[D-A2bu-Phe-gPhe-(S and R)-mLeu] with a reversed amide bond between residues four and five, and Tyr-c[D-Glu-Phe-gPhe-(L and D)-rLeu] with two reversed amide bonds between residues four and five, and between residue five and the side chain of residue two have been synthesized. The results from the guinea pig ileum (GPI) and mouse vas deferens (MVD) assays show that all analogues are superactive at either one or both opiate receptors and in general display higher activities as compared to the corresponding enkephalin analogues with a glycine at the third position. Results from the in vitro biological assays and conformational analysis using 1H-NMR spectroscopy (adjoining paper) will provide useful information to understand the role of the Phe3 aromatic side chain in dermorphin, and that of the Phe4 aromatic side chain in enkephalin, on opiate activity since these cyclic dermorphin analogues contain two Phe residues at both the third and fourth positions.  相似文献   

20.
The structural and dynamical features of the hormone α‐MSH in solution have been examined over a 100 ns time scale by using free energy molecular mechanics models at room temperature. The free energy surface has been modeled using methods from integral equation theory and the dynamics by the Langevin equation. A modification of the accessible surface area friction drag model was used to calculate the atomic friction coefficients. The molecule shows a stable β‐turn conformation in the message region and a close interaction between the side chains of His6, Phe7, and Trp9. A salt bridge between Glu5 and Arg8 was found not to be a preferred interaction, whereas a Glu5 and Lys11 salt bridge was not sampled, presumably due to relatively high free energy barriers. The message region was more conformationally rigid than the N‐terminal region. Several structural features observed here agree well with experimental results. The conformational features suggest a receptor–hormone interaction model where the hydrophobic side chains of Phe7 and Trp9 interact with the transmembrane portion of the MC1 receptor. Also, the positively charged side chain of Arg8 and the imidazole side chain of His6 may interact with the negatively charged portions of the receptor which may even be on the receptor's extracellular loops. © 1999 John Wiley & Sons, Inc. Biopoly 50: 255–272, 1999  相似文献   

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