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P Balaram - One of the best experts on this subject based on the ideXlab platform.
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Beta Turn analogues in model a ss hybrid peptides structural characterization of peptides containing ss 2 2ac6c and ss 3 3ac6c residues
2012Co-Authors: Krishnayan Basuroy, Narayanaswamy Shamala, Srinivasarao Raghothama, Appavu Rajagopal, P BalaramAbstract:The effect of gem-dialkyl substituents on the backbone conformations of Beta-amino acid residues in peptides has been investigated by using four model peptides: Boc-Xxx-Beta 2,2Ac6c(1-aminomethylcyclohexanecarboxylic acid)-NHMe (Xxx=Leu (1), Phe (2); Boc=tert-butyloxycarbonyl) and Boc-Xxx-Beta 3,3Ac6c(1-aminocyclohexaneacetic acid)-NHMe (Xxx=Leu (3), Phe (4)). Tetrasubstituted carbon atoms restrict the ranges of stereochemically allowed conformations about flanking single bonds. The crystal structure of Boc-Leu-Beta 2,2Ac6c-NHMe (1) established a C11 hydrogen-bonded Turn in the a Beta-hybrid sequence. The observed torsion angles (a(similar to-60 degrees, similar to-30 degrees), Beta(similar to-90 degrees, similar to 60 degrees, similar to-90 degrees)) corresponded to a C11 helical Turn, which was a backbone-expanded analogue of the type III Beta Turn in aa sequences. The crystal structure of the peptide Boc-Phe-Beta 3,3Ac6c-NHMe (4) established a C11 hydrogen-bonded Turn with distinctly different backbone torsion angles (a(similar to-60 degrees, similar to 120 degrees), Beta(similar to 60 degrees, ?60 degrees, similar to-60 degrees)), which corresponded to a backbone-expanded analogue of the type II Beta Turn observed in aa sequences. In peptide 4, the two molecules in the asymmetric unit adopted backbone torsion angles of opposite signs. In one of the molecules, the Phe residue adopted an unfavorable backbone conformation, with the energetic penalty being offset by a favorable aromatic interaction between proximal molecules in the crystal. NMR spectroscopy studies provided evidence for the maintenance of folded structures in solution in these a Beta-hybrid sequences.
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stabilization of Beta Turn conformations in enkephalins alpha aminoisobutyric acid analogs
International Journal of Peptide and Protein Research, 2009Co-Authors: T S Sudha, P BalaramAbstract:Stereochemical constraints have been introduced into the enkephalin backbone by substituting alpha-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 Beta-Turn centred at positions 2 and 3 is proposed for the Aib2-Gly3 analog. In the Gly2-Aib3 analog, the Beta-Turn has Aib3-Phe4 as the corner residues. The Aib2-Aib3 analog adopts a consecutive Beta-Turn or 3(10) helical conformation. High in vivo biological activity is observed for the Aib2 and Aib2-Aib3 analogs, while the Aib3 peptide is significantly less active.
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tuning the Beta Turn segment in designed peptide Beta hairpins construction of a stable type i Beta Turn nucleus and hairpin helix transition promoting segments
Biopolymers, 2007Co-Authors: Rajkishor Rai, Srinivasarao Raghothama, Rajagopalan Sridharan, P BalaramAbstract:Designed octapeptides Boc-Leu-Val-Val-Aib-$^DXxx$-Leu-Val-Val-OMe $(^DXxx=^DAla, 3a; ^DVal, 3c$ and $^DPro, 5a)$ and Boc-Leu-Phe-Val-Aib-$^DAla$-Leu-Phe-Val-OMe (3b) have been investigated to construct models of a stable type I' $\Beta$-Turn nucleated hairpin and to generate systems for investigating helix–hairpin conformational transitions. Peptide 5a, which contains a central $Aib-^D$ Pro segment, is shown to adopt a stable type I' $\Beta$-Turn nucleated hairpin structure, stabilized by four cross-strand hydrogen bonds. The stability of the structure in diverse solvents is established by the observation of all diagnostic NOEs expected in a $\Beta$-hairpin conformation. Replacement of $^DPro5$ by $^DAla/^DVal (3a-c)$ results in sequences that form $\Beta$-hairpins in hydrogen bonding solvents like $CD_3OH$ and $DMSO-d_6$. However, in $CDCl_3$ evidence for population of helical conformations is obtained. Peptide 6b (Boc-Leu-Phe-Val-Aib-Aib-Leu-Phe-Val-OMe), which contains a centrally positioned Aib-Aib segment, provides a clear example of a system, which exhibits a helical conformation in $CDCl_3$ and a significant population of both helices and hairpins in $CD_3OH$ and $DMSO-d_6$. The coexistence of multiple conformations is established by the simultaneous observation of diagnostic NOEs. Control over stereochemistry of the central $\Beta$-Turn permits generation of models for robust $\Beta$-hairpins and also for the construction of systems that may be used to probe helix–hairpin conformational transitions.
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solid state and solution conformations of a helical peptide with a central gly gly segment
Biopolymers, 1998Co-Authors: Isabella L Karle, Arindam Banerjee, Surajit Bhattacharjya, P BalaramAbstract:The influence of amino acids with contrasting con formational tendencies on the stereochemistry of oligopeptides has been investigated using an octapeptide Boc-Leu-Aib- Val-Gly-Gly-Leu-Aih-Val-OMe, which contains two helix-promoting Aib residues and a central helix-destabilizing Gly-Gly segment. Single crystal x-ray diffraction studies reveal that a 310-helix is formed up to the penultimate Aib residue, at which point there is a helix reversal in the backbone, reminiscent of a C-terminal 6 - 1 hydrogen bond. The curious feature in the crystal is the solvation of the possible 6 - 1 bond by a CH30H molecule, where the OH is inserted between O(3) and N(8) and participates in hydrogen bonds with both. The cell parameters are as follows: space group P212121, a = 10.649 (4) A, b = 15.694(5) A, c = 30.181(8) A, R = 6.7% for 3427 data ([Fo] > 3aF) observed to 0.9 A. Nuclear magnetic resonance studies in CDC13 using NHgroup solvent accessibility and nuclear Overhauser effects as probes are consistent with a 310-helical conformation. In contrast, in (CD3)2S0, unfolding of the central segment results in a multiple Beta-Turn structure, with Beta-Turn conformations populated at residues 1-2, 3-4, and 6-7. CD studies in methanol-2,2,2-trifluoroethanol (TFE) mixtures also provide evidence for a solvent-dependent structural transition. Helical conformations are populated in TFE, while type II Beta-Turn structures are favored in methanol.
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Beta Turn conformations in crystal structures of model peptides containing alpha alpha di n propylglycine and alpha alpha di n butylglycine
Biopolymers, 1995Co-Authors: Marco Crisma, Claudio Toniolo, G Valle, Sudhanand Prasad, R B Rao, P BalaramAbstract:The crystal state conformations of three peptides containing the alpha, alpha-dialkylated residues, alpha,alpha-di-n-propylglycine (Dpg) and alpha,alpha-di-n-butylglycine (Dbg), have been established by x-ray diffraction. Boc-Ala-Dpg-Ala-OMe (I) and Boc-Ala-Dbg-Ala-OMe (III) adopt distorted type II Beta-Turn conformations with Ala (1) and Dpg/Dbg (2) as the corner residues. In both peptides the conformational angles at the Dxg residue (I: phi = 66.2 degrees, psi = 19.3 degrees; III: phi = 66.5 degrees, psi = 21.1 degrees) deviate appreciably from ideal values for the i + 2 residue in a type II Beta-Turn. In both peptides the observed (N...O) distances between the Boc CO and Ala(3) NH groups are far too long (I: 3.44 Angstrom; III: 3.63 Angstrom) for an intramolecular 4 --> 1 hydrogen bond. Boc-Ala-Dpg-Ala-NHMe (II) crystallizes with two independent molecules in the asymmetric unit. Both molecules IIA and IIB adopt consecutive Beta-Turn (type III-III in IIA and type III-I in IIB) or incipient 3(10)-helical structures, stabilized by two intramolecular 4 --> 1 hydrogen bonds. In all four molecules the bond angle N-C-alpha-C' (tau) at the Dxg residues are greater than or equal to 110 degrees. The observation of conformational angles in the helical region of phi,psi space at these residues is consistent with theoretical predictions.
Padmanabhan Balaram - One of the best experts on this subject based on the ideXlab platform.
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solid state and solution conformation of boc l met aib l phe ome Beta Turn conformation of a sequence related to an active chemotactic peptide analog
International Journal of Peptide and Protein Research, 2009Co-Authors: R Bardi, Srinivasarao Raghothama, Claudio Toniolo, A M Piazzesi, P A Raj, Padmanabhan BalaramAbstract:The conformation of the peptide Boc-L-Met-Aib-L-Phe-OMe has been studied in the solid state and solution by X-ray diffraction and 1H n.m.r., respectively. The peptide differs only in the N-terminal protecting group from the biologically active chemotactic peptide analog formyl-L-Met-Aib-L-Phe-OMe. The molecules adopt a type-II Beta-Turn in the solid state with Met and Aib as the corner residues (phi Met = -51.8 degrees, psi Met = 139.5 degrees, phi Aib = 58.1 degrees, psi Aib = 37.0 degrees). A single, weak 4----1 intramolecular hydrogen bond is observed between the Boc CO and Phe NH groups (N---O 3.25 A, N-H---O 128.4 degrees). 1H n.m.r. studies, using solvent and temperature dependencies of NH chemical shifts and paramagnetic radical induced line broadening of NH resonances, suggest that the Phe NH is solvent shielded in CDCl3 and (CD3)2SO. Nuclear Overhauser effects observed between Met C alpha H and Aib NH protons provide evidence of the occurrence of Met-Aib type-II Beta-Turns in these solvents.
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tuning the β Turn segment in designed peptide β hairpins construction of a stable type i β Turn nucleus and hairpin helix transition promoting segments
Biopolymers, 2007Co-Authors: Rajkishor Rai, Srinivasarao Raghothama, Rajagopalan Sridharan, Padmanabhan BalaramAbstract:Designed octapeptides Boc-Leu-Val-Val-Aib-$^DXxx$-Leu-Val-Val-OMe $(^DXxx=^DAla, 3a; ^DVal, 3c$ and $^DPro, 5a)$ and Boc-Leu-Phe-Val-Aib-$^DAla$-Leu-Phe-Val-OMe (3b) have been investigated to construct models of a stable type I' $\Beta$-Turn nucleated hairpin and to generate systems for investigating helix–hairpin conformational transitions. Peptide 5a, which contains a central $Aib-^D$ Pro segment, is shown to adopt a stable type I' $\Beta$-Turn nucleated hairpin structure, stabilized by four cross-strand hydrogen bonds. The stability of the structure in diverse solvents is established by the observation of all diagnostic NOEs expected in a $\Beta$-hairpin conformation. Replacement of $^DPro5$ by $^DAla/^DVal (3a-c)$ results in sequences that form $\Beta$-hairpins in hydrogen bonding solvents like $CD_3OH$ and $DMSO-d_6$. However, in $CDCl_3$ evidence for population of helical conformations is obtained. Peptide 6b (Boc-Leu-Phe-Val-Aib-Aib-Leu-Phe-Val-OMe), which contains a centrally positioned Aib-Aib segment, provides a clear example of a system, which exhibits a helical conformation in $CDCl_3$ and a significant population of both helices and hairpins in $CD_3OH$ and $DMSO-d_6$. The coexistence of multiple conformations is established by the simultaneous observation of diagnostic NOEs. Control over stereochemistry of the central $\Beta$-Turn permits generation of models for robust $\Beta$-hairpins and also for the construction of systems that may be used to probe helix–hairpin conformational transitions.
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Molecular conformation and packing of peptide Beta hairpins in the solid state: structures of two synthetic octapeptides containing 1-aminocycloalkane-1-carboxylic acid residues at the i+2 position of the Beta Turn.
Chemistry: A European Journal, 2005Co-Authors: Veldore Vidya Harini, Subrayashastry Aravinda, Narayanaswamy Shamala, Padmanabhan BalaramAbstract:Peptide $\Beta$-hairpin formation is facilitated by centrally positioned D-Pro-Xxx segments. The synthetic peptides Boc-Leu-Phe-Val-D-Pro-$Ac_6c$-Leu-Phe-Val-OMe (1) and Boc-Leu-Phe-Val-d-Pro-$Ac_8c$-Leu-Phe-Val-OMe (2) were synthesized in order to explore the role of bulky 1-aminocycloalkane-1-carboxylic acid residues ($Ac_nc$, where n is the number of carbon atoms in the ring), at the $i+2$ position of the nucleating $\Beta$ Turn in peptide $\Beta$ hairpins. Peptides 1 and 2 crystallize in the monoclinic space group $P2_1$ with two molecules in the asymmetric unit. The crystal structures of 1 and 2 provide conformational parameters for four peptide hairpin molecules. In all cases, the central segments adopts a type $II'$ $\Beta$-Turn conformation, and three of the four possible cross-strand hydrogen bonds are observed. Fraying of the hairpins at the termini is accompanied by the observation of $NH \cdot\cdot\cdot \pi$ interaction between the Leu(1)NH group and Phe(7) aromatic group. Cross strand stabilizing interactions between the facing residues Phe(2) and Phe(7) are suggested by the observed orientation of aromatic rings. Anomalous far-UV CD spectra observed in solution suggest that close proximity of the Phe rings is maintained even in isolated molecules. In both peptides 1 and 2, the asymmetric unit consists of approximately orthogonal hairpins, precluding the formation of a planar $\Beta$-sheet arrangement in the solid state. Solvent molecules, one dioxane and one water in 1, three water molecules in 2, mediate peptide association. A comparison of molecular conformation and packing motifs in available $\Beta$-hairpin structures permits delineation of common features. The crystal structures of b-hairpin peptides provide a means of visualizing different modes of $\Beta$-sheet packing, which may be relevant in developing models for aggregates of polypeptides implicated in disease situations.
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designed Beta hairpin peptides with defined tight Turn stereochemistry
Biopolymers, 2001Co-Authors: G A Naganagowda, Isabella L Karle, Padmanabhan BalaramAbstract:The conformational analysis of two synthetic octapeptides, Boc–Leu–Val–Val–D-Pro–L-Ala–Leu–Val–Val–OMe (1) and Boc–Leu–Val–Val–D-Pro–D-Ala–Leu–Val–Val–OMe (2) has been carried out in order to investigate the effect of Beta-Turn stereochemistry on designed Beta-hairpin structures. Five hundred megahertz 1HNMR studies establish that both peptides 1 and 2 adopt predominantly Beta-hairpin conformations in methanol solution. Specific nuclear Overhauser effects provide evidence for a type II’ Beta-Turn conformation for the D-Pro–L-Ala segment in 1, while the NMR data suggest that the type I’ D-Pro–D-Ala b-Turn conformation predominates in peptide 2. Evidence for a minor conformation in peptide 2, in slow exchange on the NMR time scale, is also presented. Interstrand registry is demonstrated in both peptides 1 and 2. The crystal structure of 1 reveals two independent molecules in the crystallographic asymmetric unit, both of which adopt Beta-hairpin conformations nucleated by D-Pro–Lala type II’ Beta-Turns and are stabilized by three cross-strand hydrogen bonds. CD spectra for peptides and 2 show marked differences, presumably as a consequence of the superposition of spectral bands arising from both Beta-Turn and Beta-strand conformations.
Juris P Germanas - One of the best experts on this subject based on the ideXlab platform.
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novel bicyclic lactams as xaapro type vi Beta Turn mimics design synthesis and evaluation
Journal of Organic Chemistry, 1996Co-Authors: Kyonghee Kim, Jeanphilippe Dumas, Juris P GermanasAbstract:The design, enantioselective synthesis, and structural characterization of novel bicyclic lactams as peptide mimics of the type VI β Turn is described. The mimics duplicate the conformation of the ...
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design synthesis and evaluation of a novel bicyclic lactam as a gly pro type vi Beta Turn mimic
Tetrahedron Letters, 1994Co-Authors: Jeanphilippe Dumas, Juris P GermanasAbstract:Abstract The stereoselective synthesis and conformational evaluation of Gly-Pro type VI Turn mimic 7, the first mimetic to constrain the central three bonds and incorporate the side chain groups of a Beta-Turn, is described. A superimposition of the crystallographically determined structure of 7 with the structure of a typical type VI Turn revealed exceptional similarity in backbone and side chain atom positions. The temperature dependence of the chemical shift of the amide proton of the derivative 8 in DMSO confirmed the presence of a remarkably stable i, i+3 intramolecular hydrogen bond.
Javed Iqbal - One of the best experts on this subject based on the ideXlab platform.
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palladium 0 catalyzed regioselective synthesis of alpha dehydro Beta amino esters from amines and allyl acetates synthesis of a alpha dehydro Beta amino acid derived cyclic peptide as a constrained Beta Turn mimic
Journal of Organic Chemistry, 2002Co-Authors: S Rajesh, Biswadip Banerji, Javed IqbalAbstract:Acetates derived from the adducts of the Baylis-Hillman reaction can be reacted in a regioselective manner with amines in the presence of palladium(0) catalyst to afford alpha-dehydro-Beta-amino esters (2 and 3) in good yields. The regioselectivity of the reaction can be controlled by temperature and reaction medium leading to the synthesis of regioisomers 2 or 3. The alpha-dehydro-Beta-amino acid 3 is a Turn inducer, and the dipeptides 6 derived from it show the presence of an eight-membered intramolecular hydrogen bond. Also, cobalt(II) chloride catalyzes the cleavage of epoxy peptides with alpha-dehydro-Beta-amino acid derivative 3b to afford the corresponding dipeptide derivatives 8, which exhibit an intramolecular hydrogen bond and thus mimic a Beta-Turn. This intramolecular hydrogen bonding preorganizes the corresponding diallylated peptide 8c for cyclization via ring-closing metathesis to afford the cyclic peptide 9 as a constrained mimic of a Beta-Turn.
John A Robinson - One of the best experts on this subject based on the ideXlab platform.
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synthesis conformational properties and antibody recognition of peptides containing Beta Turn mimetics based on alpha alkylproline derivatives
Journal of Medicinal Chemistry, 1991Co-Authors: Mark G Hinds, John H Welsh, David M Brennand, Jenny A Fisher, Martin J Glennie, Nigel G J Richards, David L Turner, John A RobinsonAbstract:Peptide recognition by monoclonal antibodies may provide a useful model for drug development, in particular to test the effects of conformational restriction on ligand binding. We have tested the influence of novel peptide mimetics upon conformation and binding affinity for the case of monoclonal antibodies raised to a peptide antigen which displays a preference for a Beta-Turn conformation in aqueous solution. Two monoclonals were isolated that recognized the peptide Ac-Tyr-Pro-Tyr-Asp-Val-Pro-Asp-Tyr-Ala specifically at the Beta-Turn formed by Tyr-Pro-Tyr-Asp. Peptide analogues were then synthesized containing mimetics designed to stabilize this conformation. One, analogue (3), contained a spirocyclic gamma-lactam bridge between the alpha-position of proline-2 and the N atom of tyrosine-3, while another (2) contained (S)-alpha-methylproline at position 2. NMR spectroscopy and molecular modeling suggest that both analogues adopt reverse-Turn conformations stabilized relative to that in the native sequence. For the (S)-alpha-methylproline analogue binding to both monoclonal antibodies was substantially improved, compared with the native antigen, whereas the gamma-lactam analogue (3) was not recognized by either antibody. Quantitative equilibrium ultrafiltration binding assays showed that the affinities of the (S)-alpha-methylproline analogue (2) for the two antibodies were improved over those measured with the native antigen by -2.3 and -0.65 kcal/mol. The origins of these free energy differences cannot be explained wholly on the basis of presumed extra hydrophobic contacts between the new methyl substituent and the antigen binding sites. We propose that the increased conformational stability of the analogue plays a decisive role, implying that the reverse Turn detected in the native antigen, possibly a type-I Turn, is important for recognition by the two antibodies.
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synthesis conformational properties and antibody recognition of peptides containing Beta Turn mimetics based on alpha alkylproline derivatives
Journal of Medicinal Chemistry, 1991Co-Authors: Mark G Hinds, John H Welsh, David M Brennand, Jenny A Fisher, Martin J Glennie, Nigel G J Richards, David L Turner, John A RobinsonAbstract:Peptide recognition by monoclonal antibodies may provide a useful model for drug development, in particular to test the effects of conformational restriction on ligand binding. We have tested the influence of novel peptide mimetics upon conformation and binding affinity for the case of monoclonal antibodies raised to a peptide antigen which displays a preference for a β-Turn conformation in aqueous solution