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

Abstract

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.

Improved Recovery and Selectivity of Lanthanide-Ion-Binding Cyclic Peptide Hosts by Changing the Position of Acidic Amino Acids

“…To date, various organic hosts for Ln 3+ [4][5][6][7][8], peptide hosts for organic guests [9][10][11], peptide-transition metal complexes [12][13][14][15][16], and self-assembling systems [17][18][19] have been reported. In recent years, extended research on Ln porphyrins [20], lanthanide-based metal organic frameworks [21], lanthanide-based inorganic-organic hybrid materials [22], a cyclic peptide ligand for Tb ions through high-throughput screening [23], and a lanthanidebinding protein [24] have also been interesting.…”

“…Furthermore, we have tried to establish a low-cost and semi-empirical method, without a solvent molecule, to predict the recovery yield based on experiment results and the above parameters, analyzed by DFT (Density Functional Theory) calculation. The sequence of the AAs (with the exception of the acidic AAs and cysteine SS bond) and the total number of AAs (13) were identical, and thus these hosts were structural isomers. The acidic AAs in model 1 were present in a continuous sequence (2D, 3E, and 4D), those in model 2 (5D, 9E, and 10D) and model 3 (5D, 8D, and 10D) were distributed relatively more randomly, while those of model 4 were dispersed uniformly in the form of a stable tripod (4D, 8E, and l2D).…”

Lanthanide-binding peptides with two pendant aminodiacetate arms: Impact of the sequence on chelation

“…Peptides containing unnatural chelating amino acids were recently designed in our group to obtain Ln-binding peptides of enhanced stability with a ligating site embedded in the peptide framework. 12,13 Two synthetic amino acids, which bear tridentate aminodiacetate chelating groups (Ada n ) were introduced in short peptide sequences to obtain P 11 , P 22 and P 33 (Scheme 1). These compounds may be viewed as models of polyaminocarboxylate ligands, namely EDTA or TMDTA, with a peptide spacer instead of an alkyl chain.…”

“…Interestingly, the peptide P 22 provides exclusively a stable mononuclear Ln complex (β 110 = 10 12.1 ) with a triply hydrated Tb 3+ ion. 12 The use of shorter alkyl chains in P 11 seemed very promising to us as they favour the coordination of a backbone carbonyl due to the formation of a six-membered chelate ring and afford higher Scheme 1 Design of lanthanide-binding peptides incorporating Ada n residues.…”

“…In this article, we report the synthesis and Ln complexation properties of two novel hexapeptides P 12 and P 21 which contain one Ada 1 and one Ada 2 non natural chelating amino acids. These two peptides were expected to exhibit intermediate properties between P 22 and P 11 .…”