2,2,6,6-Tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid (TOAC) is a topographically and conformationally restricted, nitroxide containing, C(alpha)-tetrasubstituted alpha-amino acid. Here, we describe the molecular and crystal structures, as determined by X-ray diffraction analyses, of a TOAC terminally protected derivative, the cyclic dipeptide c(TOAC)(2).1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) solvate, and five TOAC-containing, terminally protected, linear peptides ranging in length from tetra- to hepta-peptides. Incipient and fully developed, regular or distorted 3(10)-helical structures are formed by the linear peptides. A detailed discussion on the average geometry and preferred conformation for the TOAC piperidine ring is also reported. The X-ray diffraction structure of an intramolecularly cyclized side product resulting from a C-activated TOAC residue has also been determined.
"position (D'Amore et al. 2003). In addition, the crystallographic characterization of some TOAC derivatives showed the piperidine ring in an approximate chair conformation, with the αamino group in the axial position and the α-carboxyl group in the equatorial position (Flippen-Anderson et al. 1996; Crisma et al. 2005). The nitroxyl group presents two absorption bands in the UV-visible region, ascribed to the n → π* (ʎ0420–450 nm, ɛ05–20 L mol −1 cm "
[Show abstract][Hide abstract] ABSTRACT: We review work on the paramagnetic amino acid 2,2,6,6-tetramethyl-N-oxyl-4-amino-4-carboxylic acid, TOAC, and its applications in studies of peptides and peptide synthesis. TOAC was the first spin label probe incorporated in peptides by means of a peptide bond. In view of the rigid character of this cyclic molecule and its attachment to the peptide backbone via a peptide bond, TOAC incorporation has been very useful to analyze backbone dynamics and peptide secondary structure. Many of these studies were performed making use of EPR spectroscopy, but other physical techniques, such as X-ray crystallography, CD, fluorescence, NMR, and FT-IR, have been employed. The use of double-labeled synthetic peptides has allowed the investigation of their secondary structure. A large number of studies have focused on the interaction of peptides, both synthetic and biologically active, with membranes. In the latter case, work has been reported on ligands and fragments of GPCR, host defense peptides, phospholamban, and β-amyloid. EPR studies of macroscopically aligned samples have provided information on the orientation of peptides in membranes. More recent studies have focused on peptide-protein and peptide-nucleic acid interactions. Moreover, TOAC has been shown to be a valuable probe for paramagnetic relaxation enhancement NMR studies of the interaction of labeled peptides with proteins. The growth of the number of TOAC-related publications suggests that this unnatural amino acid will find increasing applications in the future.
[Show abstract][Hide abstract] ABSTRACT: Time-resolved spectroscopies, spanning from the nanosecond to the microsecond time regime, coupled with molecular mechanics calculations, allowed us to assess the most populated conformations in solution of a series of analogues of trichogin GA IV, a natural undecapeptide showing significant antimicrobial activity. This peptide is characterized by a high content of the conformationally constrained alpha-aminoisobutyric acid and by a glycine-glycine motif in the central part of the sequence. Nanosecond time-resolved fluorescence experiments were performed to determine the conformational properties of the peptide analogues in solution, while transient absorption measurements allowed us to study the peptide dynamics on the microsecond time scale. Because the peptides examined were functionalized by a fluorescent probe at the N-terminus and a nitroxide quencher placed along the backbone at three different positions, the distance-dependent fluorophore-quencher interaction was exploited to obtain a deeper insight into their three-dimensional structural and dynamical properties. Further information on the conformational and dynamical features was obtained by photophysical experiments as a function of the viscosity and polarity of the medium. Taken together, the results revealed a transition from an elongated, helical conformation to a family of compact, folded structures mimicking a helix-turn-helix motif, which may represent a model of the early steps of the protein hydrophobic collapse.
The Journal of Physical Chemistry B 12/2006; 110(45):22834-41. DOI:10.1021/jp063078w · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The crystal-state conformations of the hexapeptide amide Pht-(Aib)(6)-NH-C(CH(3))(2)-O-OtBu (7), the hexapeptide Ac-L-aIle-(Aib)(5)-OtBu (6), the pentapeptide Z-(Aib)(3)-L-Glu(OtBu)-Aib-O-(CH(2))(2)-(1)Nap (5), the tetrapeptides Z-(Aib)(2)-L-His(N(tau)-Trt)-Aib-OMe (4 I) and Z-(Aib)(2)-L-Nva-Aib-OtBu (4 II), the tripeptide Pyr-(Aib)(3)-OtBu (3 I), the dipeptide amides Pyr-(Aib)(2)-(4)NH-TEMPO (3 II) and Piv-(Aib)(2)-NH-C(CH(3))(2)-O-OtBu (3 III), and the dipeptides Pht-Aib-betaAc(6)c-OtBu (2 I), Pht-Aib-NH-C(CH(3))(2)-O-OtBu (2 II) and Boc-gGly-mAib-OH (2 III) have been determined by X-ray diffraction analyses. All peptides investigated are characterized by one or more turn/helix forming Aib residues. Except the three short dipeptides, all are folded into C==O...H--N intramolecularly H-bonded 3(10)-helices, or into various types of beta-turns. In the structure of 6, two independent molecules of opposite screw sense were observed in the asymmetric unit, generating diastereomeric 3(10)-helices.
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