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Side-chain Orientation (side-chain + orientation)
Selected AbstractsStructure,function relationship studies of PTH(1,11) analogues containing sterically hindered dipeptide mimeticsJOURNAL OF PEPTIDE SCIENCE, Issue 8 2007Nereo Fiori Abstract The N -terminal 1,34 fragment of parathyroid hormone (PTH) is fully active in vitro and in vivo and reproduces all biological responses characteristic of the native intact PTH. In order to develop safer and non-parenteral PTH-like bone anabolic agents, we have studied the effect of introducing conformationally constrained dipeptide mimetics into the N -terminal portion of PTH in an effort to generate miniaturized PTH-mimetics. To this end, we have synthesized and conformationally and biologically characterized PTH(1,11) analogues containing 3R -carboxy-6S -amino-7,5-bicyclic thiazolidinlactam (7,5-bTL), a rigidified dipeptide mimetic unit. The wild type sequence of PTH(1,11) is H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-NH2. The following pseudo-undecapeptides were prepared: [Ala1, 7,5-bTL3, 4, Nle8, Arg11]hPTH(1,11)NH2 (I); [Ala1, 7,5-bTL6, 7, Nle8, Arg11]hPTH(1,11)NH2 (II); [Ala1, Nle8, 7,5-bTL9, 10, Arg11]hPTH(1,11)NH2 (III). In aqueous solution containing 20% TFE, only analogue I exhibited the typical CD pattern of the ,-helical conformation. NMR experiments and molecular dynamics calculations located the ,-helical stretch in the sequence Ile5 -His9. The dipeptide mimetic unit 7,5-bTL induces a type III ,-turn, occupying the positions i , 1 and i of the turn. Analogue II exhibited an equilibrium between a type I ,-turn and an ,-helix, and analogue III did not show any ordered structure. Biological tests revealed poor activity for all analogues (EC50 > 0.1 mM). Apparently, the relative side-chain orientation of Val2, Ile5 and Met8 can be critical for effective analogue-receptor interaction. Considering helicity as an essential property to obtain active PTH agonists, one must decorate the correctly positioned dipeptide mimetic azabicycloalkane scaffold with substitutions corresponding to the displaced amino acids. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [source] The relative orientation of the Arg and Asp side chains defined by a pseudodihedral angle as a key criterion for evaluating the structure,activity relationship of RGD peptidesJOURNAL OF PEPTIDE SCIENCE, Issue 8 2004Sarantos Kostidis Abstract The ability of an integrin to distinguish between the RGD-containing extracellular matrix proteins is thought to be due partially to the variety of RGD conformations. Three criteria have been proposed for the evaluation of the structure,activity relationship of RGD-containing peptides. These include: (i) the distance between the charged centres, (ii) the distance between the Arg C, and Asp C, atoms, and (iii) the pseudo-dihedral angle defining the Arg and Asp side-chain orientation formed by the Arg C,, Arg C,, Asp C, and Asp C, atoms. A comparative conformation,activity study was performed between linear RGD peptides and strongly constrained cyclic (S,S) -CDC- bearing compounds, which cover a wide range of inhibition potency of platelet aggregation. It is concluded that the fulfilment of the ,45° , pseudo-dihedral angle , +45° criterion is a prerequisite for an RGD compound to exhibit inhibitory activity. Once this criterion is accomplished, the longer the distance between the charged centres and/or between the Arg and Asp C, atoms, the higher is the biological activity. In addition, the stronger the ionic interaction between Arg and Asp charged side chains, the lower the anti-aggregatory activity. Copyright © 2004 European Peptide Society and John Wiley & Sons, Ltd. [source] Probing multiple effects on 15N, 13C,, 13C,, and 13C, chemical shifts in peptides using density functional theoryBIOPOLYMERS, Issue 6 2002Xiao-Ping Xu Abstract We have used density functional calculations on model peptides to study conformational effects on 15N, 13C,, 13C,, and 13C, chemical shifts, associated with hydrogen bonding, backbone conformation, and side-chain orientation. The results show a significant dependence on the backbone torsion angles of the nearest three residues. Contributions to 15N chemical shifts from hydrogen bonding (up to 8 ppm), backbone conformation (up to 13 ppm), side-chain orientation and neighborhood residue effects (up to 22 ppm) are significant, and a unified theory will be required to account for their behavior in proteins. In contrast to this, the dependence on sequence and hydrogen bonding is much less for 13C, and 13C, chemical shifts (<0.5 ppm), and moderate for carbonyl carbon shifts (<2 ppm). The effects of side-chain orientation are mainly limited to the residue itself for both nitrogen and carbon, but the ,1 effect is also significant for the nitrogen shift of the following residue and for the 13C, shift of the preceding residue. The calculated results are used, in conjunction with an additive model of chemical shift contributions, to create an algorithm for prediction of 15N and 13C shifts in proteins from their structure; this includes a model to extrapolate results to regions of torsion angle space that have not been explicitly studied by density functional theory (DFT) calculations. Crystal structures of 20 proteins with measured shifts have been used to test the prediction scheme. Root mean square deviations between calculated and experimental shifts 2.71, 1.22, 1.31, and 1.28 ppm for N, C,, C,, and C,, respectively. This prediction algorithm should be helpful in NMR assignment, crystal and solution structure comparison, and structure refinement. © 2002 Wiley Periodicals, Inc. Biopolymers 65: 408,423, 2002 [source] Structural studies of a baboon (Papio sp.) plasma protein inhibitor of cholesteryl ester transferasePROTEIN SCIENCE, Issue 8 2000Garry W. Buchko Abstract A 38-residue protein associated with cholesteryl ester transfer inhibition has been identified in baboons (Papio sp.). The cholesteryl ester transfer inhibitor protein (CETIP) corresponds to the N-terminus of baboon apoC-I. Relative to CETIP, baboon apoC-I is a weak inhibitor of baboon cholesteryl ester transferase (CET). To study the structural features responsible for CET inhibition, CETIP was synthesized by solid-phase methods. Using sodium dodecyl sulfate (SDS) to model the lipoprotein environment, the solution structure of CETIP was probed by optical and 1HNMR spectroscopy. Circular dichroism data show that the protein lacks a well-defined structure in water but, upon the addition of SDS, becomes helical (56%). A small blue shift of 8 nm was observed in the intrinsic tryptophan fluorescence of CETIP in the presence of saturating amounts of SDS, suggesting that tryptophan-23 is not buried deeply in the lipid environment. The helical nature of CETIP in the presence of SDS was confirmed by upfield 1H, secondary shifts and an average solution structure determined by distance geometry/simulated annealing calculations using 476 NOE-based distance restraints. The backbone (N , C, , C, = O ) root-mean-square deviation of an ensemble of 17 out of 25 calculated structures superimposed on the average structure was 1.06 ± 0.30 Å using residues V4-P35 and 0.51 ± 0.17 Å using residues A7-S32. Although the side-chain orientations fit the basic description of a class A amphipathic helix, both intramolecular salt bridge formation and "snorkeling" of basic side chains toward the polar face play minor, if any, roles in stabilizing the lipid-bound amphipathic structure. Conformational features of the calculated structures for CETIP are discussed relative to models of CETIP inhibition of cholesteryl ester transferase. [source] Antimicrobial peptide RP-1 structure and interactions with anionic versus zwitterionic micellesBIOPOLYMERS, Issue 1 2009Sarah Bourbigot Abstract Topologically, platelet factor-4 kinocidins consist of distinct N-terminal extended, C-terminal helical, and interposing ,-core structural domains. The C-terminal ,-helices autonomously confer direct microbicidal activity, and the synthetic antimicrobial peptide RP-1 is modeled upon these domains. In this study, the structure of RP-1 was assessed using several complementary techniques. The high-resolution structure of RP-1 was determined by NMR in anionic sodium dodecyl sulfate (SDS) and zwitterionic dodecylphosphocholine (DPC) micelles, which approximate prokaryotic and eukaryotic membranes, respectively. NMR data indicate the peptide assumes an amphipathic ,-helical backbone conformation in both micelle environments. However, small differences were observed in the side-chain orientations of lysine, tyrosine, and phenylalanine residues in SDS versus DPC environments. NMR experiments with a paramagnetic probe indicated differences in positioning of the peptide within the two micelle types. Molecular dynamics (MD) simulations of the peptide in both micelle types were also performed to add insight into the peptide/micelle interactions and to assess the validity of this technique to predict the structure of peptides in complex with micelles. MD independently predicted RP-1 to interact only peripherally with the DPC micelle, leaving its spherical shape intact. In contrast, RP-1 entered deeply into and significantly distorted the SDS micelle. Overall, the experimental and MD results support a preferential specificity of RP-1 for anionic membranes over zwitterionic membranes. This specificity likely derives from differences in RP-1 interaction with distinct lipid systems, including subtle differences in side chain orientations, rather than gross changes in RP-1 structure in the two lipid environments. © 2008 Wiley Periodicals, Inc. Biopolymers 91: 1,13, 2009. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] | ||||||||||