Synthesis of peptides containing unnatural, metal-ligating residues: aminodiacetic acid as a peptide side chain

Ruan, Fuqiang; Chen, Yanqiu; Itoh, Katsumi; Sasaki, Tokio; Hopkins, Paul B.

doi:10.1021/jo00014a006

Cited by 48 publications

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“…[17] However, undesired side-reactions such as trifluoroacetate capping of the peptide were reported to occur using this Boc strategy. Other authors subsequently published the procedure for the synthesis of Ada n -containing peptides using Fmoc-Ada n -OH protected synthons.…”

Section: Resultsmentioning

confidence: 99%

“…[16] Among metal-chelating amino acid side-chains, aminodiacetate groups have attracted our attention. [17][18][19] The corresponding residues are referred to as Ada n (n being the length of the alkyl chain separating the peptide backbone from the aminodiacetate nitrogen). They have been shown to stabilize helical structures in synthetic peptides through divalent-metal-ion coordination.…”

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confidence: 99%

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Lanthanide(III) Complexes with Two Hexapeptides Incorporating Unnatural Chelating Amino Acids: Secondary Structure and Stability

Cisnetti

Gateau

Lebrun

et al. 2009

Chemistry A European J

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Unnatural metal-chelating amino acids bearing aminodiacetate side-chains have been introduced into two hexapeptides to obtain efficient lanthanide-binding peptides. The synthesis of the enantiopure Fmoc-Ada(n)(tBu)2-OH synthons is described with overall yields of 32 and 50% for n=2 and n=3 side-chain carbon atoms, respectively. The two peptides AcWAda(n)PGAda(n)GNH2 (Pn) were synthesized from the protected synthons by standard solid-phase peptide synthesis. Studies of the lanthanide complexes of the two peptides Pn by luminescence titrations, mass spectrometry, circular dichroism, and solution NMR spectroscopy demonstrate that the Ada(n) chain length has a dramatic effect on the complexation properties. Indeed, the flexible compound P3 forms a mononuclear complex of moderate stability (beta11=10(9.9)), which tends to transform into a binuclear species in the presence of excess of the metal ion. Interestingly, the more compact peptide P2 provides stable Ln3+ complexes with the exclusive formation of the mononuclear LnP2 adduct. The stability constant of TbP2 is two orders of magnitude higher (beta11=10(12.1)) than that measured for P3. The 800 MHz NMR spectrum of the La3+ complex of P2 evidences a well-defined type II beta-turn as well as a hydrophobic Trp(indole)-Pro interaction. These interactions exemplify the non-innocent character of the peptide spacer in the complex LaP2 as well as the role of a peptide secondary structure in the stabilization of metal complexes.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Lanthanide(III) Complexes with Two Hexapeptides Incorporating Unnatural Chelating Amino Acids: Secondary Structure and Stability

Cisnetti

Gateau

Lebrun

et al. 2009

Chemistry A European J

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“…The a-helix, first proposed as a model structure by Pauling et al (4) and experimentally studied by Perutz (5) is a landmark in protein secondary structures. Empirical predictions (6,7) and experimental studies (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) have provided a wealth of information on helix formation in peptides and polypeptides. These studies showed the variations in helix propensities of the amino acids (8)(9)(10)(11)(12), as well as the helix-stabilizing role of charged side-chain-helix dipole interactions (13), salt bridges (14), disulfide linkages (15), hydrophobic periodicity (16), aromatic interactions (17), and metal chelation (18).…”

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Stabilization of alpha-helical structures in short peptides via end capping.

Forood

Feliciano

Nambiar

1993

Proc. Natl. Acad. Sci. U.S.A.

238

210

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The a-helix-stabilizing effect of different amino acid residues at the helical termini of short peptides in aqueous solution has been determined. Several dodecapeptides containing alanine, asparagine, aspartate, glutamine, glutamate, and serine at the amino terminus and arginine, lysine, and alanine at the carboxyl terminus were synthesized, and the a-helical content of each peptide was measured by using circular dichroism spectroscopy. The trend in a-helix-inducing ability of these amino acids was found to be as follows: In an a-helix, NH donors of the first four residues and CO acceptors of the last four residues lack intrahelical hydrogenbond partners. Presta and Rose (19) hypothesized that a necessary condition for helix formation is the presence of residues flanking the helix termini that have side chains to supply hydrogen-bond partners for unpaired main-chain NH and CO groups. Richardson and Richardson (20), by surveying several proteins of known structures, showed that at the amino termini of helices, there is a preponderance of amino acids with side chains that could hydrogen-bond with the free NH groups of the helix. Gierasch and coworkers (21) have shown that side-chain-backbone hydrogen bonding, as proposed by Presta and Rose, may also stabilize helix formation in peptides. Site-directed mutagenesis studies involving the amino-terminal residues of a-helices in native proteins have shown the significance of such hydrogen bonding in protein stability (22,23).We decided to test the Presta and Rose hypothesis in a peptide designed to fold into an isolated a-helix (24). The rationale for the design is as follows. (i) We chose a short a-helical segment (12 residues) resembling most a-helices found in native proteins. Further, we expected the capping effects to be more prominent in a short peptide. (ii) We introduced a proline and a glycine, amino acids traditionally known to be helix breakers, at positions 2 and 11, respectively, to demarcate the helical ends (25). We also hoped that the presence of the helix breakers might enable the side chains of the end residues to turn around and hydrogen-bond with the free NH and CO groups at the helical termini. (iii) The presence of a glutamate at position 4 and a lysine at position 7 increases solubility of the peptide and may also stabilize the helix by salt bridge formation (14). (iv) The rest of the amino acids were chosen to be alanine, which has a high tendency to form a-helices (26). (v) The respective positively and negatively charged side chains of arginine at the carboxyl end and aspartate at the amino end are expected to interact favorably with the helical dipole and stabilize the a-helix (13). (vi) The negatively charged carboxyl group of Arg-12 is amidated to eliminate repulsive interactions -between itself and the negative pole of the helical dipole. (vii) The a amino group of residue 1 was not acylated to prevent such an amide carbonyl from hydrogen bonding with the free NH groups at the amino terminus. The sequences of our model peptide an...

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“…Design and synthesis of Ida n -incorporated S-peptide by the Fmoc strategy: Although Hopkins used Boc chemistry to insert Ida n into a model peptide, [8] we found Fmoc (fluorenylmethyloxycarbonyl) chemistry for mutant S-peptide synthesis to be more feasible. In order to allow Ida n access to the solid-phase peptide synthesizer for the Fmoc method, we synthesized the unnatural amino acid 1 (Ida 4 ), protected by a Fmoc group at the N-terminal and by tert-butyl groups at the iminodiacetic acid ends, as shown in Scheme 1.…”

Section: Resultsmentioning

confidence: 99%

Single- or Dual-Mode Switching of Semisynthetic Ribonuclease S′ with an Iminodiacetic Acid Moiety in Response to the Copper(II) Concentration

et al. 1999

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Abstract:Ribonuclease S' bearing iminodiacetic acid as a metal-binding site was designed and semisynthesized by self-assembly of native S-protein with chemically modified S-peptide. Iminodiacetic acid-appended amino acid (Ida 4 ) was synthesized and incorporated into the S-peptide sequence by solid-phase peptide synthesis based on Fmoc chemistry at a single site or double sites of the solvent-exposed side of the S-peptide. Circular dichroism (CD) spectroscopy of these S-peptides confirmed that the Cu II ion induced an increase or decrease of a-helix conformation depending on the replacement position. S-Peptide/Sprotein titration monitored by conventional enzymatic activity and UV or CD spectroscopy demonstrated that various S-peptides form a stable complex (Ida 4 ± RNase S') with S-protein, except when Met13 and Asp14 are replaced with Ida 4

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Synthesis of peptides containing unnatural, metal-ligating residues: aminodiacetic acid as a peptide side chain

Cited by 48 publications

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Lanthanide(III) Complexes with Two Hexapeptides Incorporating Unnatural Chelating Amino Acids: Secondary Structure and Stability

Lanthanide(III) Complexes with Two Hexapeptides Incorporating Unnatural Chelating Amino Acids: Secondary Structure and Stability

Stabilization of alpha-helical structures in short peptides via end capping.

Single- or Dual-Mode Switching of Semisynthetic Ribonuclease S′ with an Iminodiacetic Acid Moiety in Response to the Copper(II) Concentration

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