摘要:

AbstractA cyclic hirudin C‐terminal fragment, even truncated to eight residues, retains higher activity in binding to thrombin compared with its linear analogue of the same peptide length. In this paper, we report the results of a conformational study of a cyclic hirudin peptide 55–62 bound to the exosite of thrombin. Based on transferred NOE data and molecular modeling, conformation of the 18‐membered ring was well defined with little mobility in the loop region. The backbone conformations of residues Glu (58) to Lys (61) are very similar to those in a native 11‐residue linear peptide in the thrombin‐bound state [Ni et al. (1990)Biochemistry, vol. 29, pp. 4479–4489; Skrzypczak‐Jankun et al. (1991)Journal of Molecular Biology, vol. 221, pp. 1379–1393]. The side chain of Ile (59), the most critical residue, assumes agauche−conformation, as observed in linear hirudin peptides. The bound conformations of residues Phe (56) and Glu (57) are defined by an iterative procedure involving the matching of computed and experimental transferred NOE intensities. The exosite of thrombin appears to be very specific to both the backbone and the side‐chain conformations of the hirudin C‐terminal peptides, especially those of residues Phe (56) and Ile (59). © 199

ISSN:0006-3525    

DOI:10.1002/bip.360340902

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe crystal structure of a dipeptideL‐leucyl–L‐leucine (C12H24N2O3) has been determined. The crystals are monoclinic, space group P21, witha= 5.434(4) Å,b= 15.712(7) Å,c= 11.275(2) Å, β = 100.41(1)°, andZ= 2. The crystals contain one molecule of dimethyl sulfoxide (DMSO) as solvent of crystallization for each dipeptide molecule. The structure has been solved by direct methods and refined to a finalRindex of 0.059 for 920 reflections (sinθ/λ ⩽ 0.60 Å−1) withI⩾ 2σ (I). Thetranspeptide unit shows substantial degree of non‐planarity (Δω = 14°). The peptide backbone adopts an extended conformation with torsion angles of ψ1= 138(1)°, ω1= 166(1)°, ϕ2= − 149.3(7)°, ψ21= 164.2(7)°, and ψ22= − 15(1)°. For the first leucyl residue, the side‐chain conformation is specified by the torsion angles1χ1= 176.7(7)°,1χ21= 62(1)°,1χ22= − 177.4(8)°; the second leucyl residue adopts a Sterically unfavorable conformation with2χ1= 61(1)°,2χ21= 97(1)°, and2χ22= −151(1)°. The packing involves head‐to‐tail interaction of peptide molecules and segregation of polar and nonpolar regions. The DMSO molecule is strongly hydrogen b

ISSN:0006-3525    

DOI:10.1002/bip.360340903

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractA dynamical model for an N‐terminal fragment of the human CD4 protein has been determined by computer simulation. The protein has been studied both in vacuo and in solution. Data from both simulations agree moderately well with each other and with the crystal structure. All elements of secondary structure were retained during simulation. Point mutation and sequence replacement studies have shown that a loop in CD4, residues 40–52, is involved in binding with gp120, the human immunodeficiency virus surface glycoprotein.1,2Our results show that the gp120‐binding loop and a few regions which bind to monoclonal antibodies and class II MHC molecules are the most highly motile areas of the protein. These results are consistent with the suggestion that CD4 binds to target molecules by using induced‐fit contacts. © 1994 John Wiley&S

ISSN:0006-3525    

DOI:10.1002/bip.360340904

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractBy use of a combination of1H nuclear Overhauser effect measurements, restrained molecular dynamics simulations, and13C spin–lattice relaxation time measurements, the solution behavior of the glycan moiety of a complex glycoinositol phospholipid termed G1PL‐6, from the protozoan parasiteLeishmania majorhas been determined. The glycan moiety of GIPL‐6 has the following structure, which is characterized by the presence of an internal β‐galactofuranose residue:The glycan does not adopt a single conformation in solution, due to significant torsional variations about the two phosphodiester linkages and certain glycosidic linking in the molecule. The present of the internal galactofuranose residue results in an average solution conformation of the oligosaccharide, which resembles a “hairpin,” with the galactofuranose residue at the apex. © 1994 John Wi

ISSN:0006-3525    

DOI:10.1002/bip.360340905

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe solution structure of a hexapeptide, cyclo(Gln‐Trp‐Phe‐Gly‐Leu‐Met), which is a selective NK‐2 antagonist, has been studied by a combination of two‐dimensional nmr and molecular dynamics (MD) techniques. The simulation based on nmr and MD data resulted in the convergence to a family of structures. Free molecular dynamics for 50 ps in the presence of DMSO solvent molecules shows that the structure is energetically stable. One intramolecular hydrogen bond between the amide proton of Gin and the carbonyl oxygen of Gly was revealed. This result is consistent with the results from the measurement of the temperature coefficient of the amide protons. The extent of intermolecular hydrogen bonding between the amide protons of the peptide and DMSO was also revealed by the free MD simulation. The resulting structure of the cyclic peptide contains a variation type I′ β‐turn in the Gly‐Leu‐Met‐Gln segment. Comparison of the structure of this peptide with that of other NK‐2 antagonist cyclic hexapeptides was made, and the activity of cyclic antagonists appears to be inversely related to the conformational rigidity of the cyclic peptides.

ISSN:0006-3525    

DOI:10.1002/bip.360340906

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe solution behavior of the single‐stranded CCAAT‐containing octamer1, d(AGCCAATA), that comprises part of the nuclear factor I (NF‐I) recognition site at the origin of replication of human adenovirus has been studied by nmr spectroscopy at 500 and 600 MHz. Proton resonance assignments for1were aided by selective13C enrichment at C1′ of A1or A5. High‐resolution13C‐1H heteronuclear multiple‐bond coherence spectra of the13C‐labeled oligomers permitted the selective detection of furanosyl ring protons within each labeled residue due to short‐ and long‐range13C‐1H couplings to the enriched C1′. The resulting assignments provided firm starting points in the interpretation of double quantum filtered correlated spectra, yielding information supplemented by total correlated spectroscopy (TOCSY) and rotating frame nuclear Overhauser effect spectroscopic data to completely assign the1H‐nmr spectrum of1and extract3JHHvalues for furanose con‐formational analysis. Several13C‐1H spin‐coupling constants within the13C‐enriched A1or A5residues were measured from cross‐peak shifts in TOCSY spectra, and their signs determined by inspection of the relative orientations of these shifts.1H‐2‐H and13C‐1H spin‐couplings both indicate a preference (>75%) for south (C2′‐endo) conformations by the f

ISSN:0006-3525    

DOI:10.1002/bip.360340907

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractSequence repeats constituting the telomeric regions of chromosomes are known to adopt a variety of unusual structures, consisting of a G tetraplex stem and short stretches of thymines or thymines and adenines forming loops over the stem. Detailed model building and molecular mechanics studies have been carried out for these telomeric sequences to elucidate different types of loop orientations and possible conformations of thymines in the loop. The model building studies indicate that a minimum oftwothymines have to be interspersed between guanine stretches to form folded‐back structures with loops across adjacent strands in a G tetraplex (both over the small as well as large groove), while the minimum number of thymines required to build a loop across the diagonal strands in a G tetraplex isthree. For two repeat sequences, these hairpins, resulting from different types of folding, can dimerize in three distinct ways—i.e., with loops across adjacent strands and on same side, with loops across adjacent strands and on opposite sides, and with loops across diagonal strands and on opposite sides—to form hairpin dimer structures. Energy minimization studies indicate that all possible hairpin dimers have very similar total energy values, though different structures are stabilized by different types of interactions. When the two loops are on the same side, in the hairpin dimer structures of d(G4TnG4), the thymines form favorably stacked tetrads in the loop region and there is interloop hydrogen bonding involving two hydrogen bonds for each thymine–thymine pair. Our molecular mechanics calculations on various folded‐back as well as parallel tetraplex structures of these telomeric sequences provide a theoretical rationale for the experimentally observed feature that the presence of intervening thymine stretches stabilizes folded‐back structures, while isolated stretches of guanines adopt a parallel tetraplex structure. © 1994 John Wil

ISSN:0006-3525    

DOI:10.1002/bip.360340908

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractA 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 containtranspeptide 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 Phe3residue. Analogous studies performed with the structurally related μ receptor‐selective μ agonist H‐Tyr‐D‐Tic‐Phe‐NH2resulted 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‐NH2revealed that the Phe3residues of theL‐Tic‐ and theD‐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 Tyr1and Tic2aromatic rings and the N‐terminal amino group or the Tyr1and Phe3aromatic 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 recept

ISSN:0006-3525    

DOI:10.1002/bip.360340909

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractA 17‐residue disulfide‐bridged peptide (PAK 128–144) corresponding to the C‐terminus ofPseudomonas aeruginosapilin strain K has been studied by one‐ and two‐dimensional nmr techniques. This synthetic immunogen has been found to exist as two distinct conformations in solution, which have been demonstrated to arise as a result of the isomerization of the I138‐P139amide bond. The two isomers occur in the ratio of 3 : 1transtocisat 5°C. Sequential assignments for both forms have been accomplished through the use of nuclear Overhauser enhancement spectroscopy (NOESY) spectra and most side‐chain resonances have been assigned using a combination of correlated spectroscopy, total correlated spectroscopy, and NOESY spectra. The presence of thecisisomer, which is considerably more predominant in the oxidized peptide, was confirmed by the observation of the characteristic NOEs between P139and the preceding residue. Further corroboration was given by the disappearance of thecisresonances in the spectrum of the P139A analogue of PAK 128–144. From observation of the differences in the chemical shifts and amide proton temperature coefficients of the two isomers, it is apparent that the two forms differ markedly in their solution conformation. The biological implications of the isomerization are discussed. © 1994 J

ISSN:0006-3525    

DOI:10.1002/bip.360340910

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractA conformational search of two similar κ‐selective cyclic Dynorphin A (Dyn A) analogues is presented. Dyn A1–11‐NH2(1) and Dyn A1–11‐NH2(2) are not only highly potent κ‐selective peptides but they also exhibit exceptional selectivity for κ receptors in the central (brain) vs. the peripheral (ileum) systems. Molecular mechanics systematic searching of the conformational preferences of the cyclic moieties of1and2produced 741 and 1003 starting ring structures, which were minimized at two dielectric constants of 2.0 and 80.0 in the AMBER force field. By rms superimposition, these low energy structures were grouped into conformational families for each ring system minimized at each dielectric. Comparison of the lowest energy structure of each of these families demonstrated that two (labeled A and B) were found as low energy ring systems for both1and2after minimization at either dielectric constant. These two structures are thus predicted to be the putative binding conformations for Dynorphin A at receptors in the brain. Interestingly, one of these putative binding structures exhibited an α‐helical conformation in the disulfide bridged ring that has not been observed for small cyclic peptides of this nature before. Molecular dynamics simulation of the helical binding structures indicated that the helical configuration in2is lower in energy and is more confor‐mationally stable than that of1. We correlate this with the increased selectivity and potency of2for κ receptors in the brain compared to the periphery, implying that this may be due to an α‐helical conformation in the cyclized address or helical induction in the message sequence. © 1

ISSN:0006-3525    

DOI:10.1002/bip.360340911

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY