Conformational Stability of Helical Peptides Containing a Thioamide Linkage

Miwa, Julia H.; Pallivathucal, Letha; Gowda, Shyla; Lee, Katherine E.

doi:10.1021/ol027056d

Cited by 76 publications

(76 citation statements)

References 19 publications

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“…Miwa and co-workers have demonstrated the possibility of incorporating thioamide linkages in b sheet and a helix secondary structures. [15,16] A b sheet structure adopted by a thiopeptide is very similar to that of the corresponding oxopeptide, while a single thio substitution even increases the thermal stability of an a helix. This is due to stronger acidity of the thioamide hydrogen, as a consequence of the longer C= S bond and the lower electronegativity of sulfur.…”

Section: Introductionmentioning

confidence: 98%

Coexistence of Hydrogen‐Bonded Loop and Extended Tetrapeptide Conformations

Cervetto

Pfister

Kolano

et al. 2007

Chemistry A European J

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The conformations of a protected tetrathiopeptide have been analysed by isotope labelling and two-dimensional infrared spectroscopy (2D-IR). It has been found that Boc-Ala-Gly(=S)-Ala-Aib-OMe in acetonitrile, as well as its oxopeptide analogue, can adopt a hydrogen-bonded loop conformation in coexistence with less restricted structures. The two types of conformations interconvert too quickly to be resolved on the nuclear magnetic resonance (NMR) timescale, but give rise to different cross peaks in two-dimensional infrared spectra. The hydrogen bond between the Boc terminal group and the amide proton of Aib can be broken by photoisomerisation of the thioamide bond.

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Section: Introductionmentioning

confidence: 98%

Coexistence of Hydrogen‐Bonded Loop and Extended Tetrapeptide Conformations

Cervetto

Pfister

Kolano

et al. 2007

Chemistry A European J

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“…Thioxo-peptide bonds slightly restrict conformational space of the polypeptide backbone (16)(17)(18) but are tolerated in α-helices and β-sheets (19)(20)(21). Thioxylation destabilizes α-helices by about 7 kJ∕mol relative to an oxo-amide bond (21), which makes thioxo-peptide bonds a perfect tool to monitor formation of individual backbone hydrogen bonds during protein folding reactions.…”

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confidence: 99%

Mapping backbone and side-chain interactions in the transition state of a coupled protein folding and binding reaction

Bachmann

Wildemann

Praetorius

et al. 2011

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

116

147

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Understanding the mechanism of protein folding requires a detailed knowledge of the structural properties of the barriers separating unfolded from native conformations. The S-peptide from ribonuclease S forms its α-helical structure only upon binding to the folded S-protein. We characterized the transition state for this binding-induced folding reaction at high resolution by determining the effect of site-specific backbone thioxylation and side-chain modifications on the kinetics and thermodynamics of the reaction, which allows us to monitor formation of backbone hydrogen bonds and side-chain interactions in the transition state. The experiments reveal that α-helical structure in the S-peptide is absent in the transition state of binding. Recognition between the unfolded S-peptide and the S-protein is mediated by loosely packed hydrophobic side-chain interactions in two well defined regions on the S-peptide. Close packing and helix formation occurs rapidly after binding. Introducing hydrophobic residues at positions outside the recognition region can drastically slow down association.phi-value analysis | protein-protein interaction | encounter complex formation | thioxo peptide bond C onformational changes in proteins play an important role in many biological processes. A detailed understanding of the mechanism of conformational transitions requires knowledge of the structural and dynamic properties of the initial and final states as well as the characterization of the transition barrier separating them. Site-directed mutagenesis proved a powerful tool to determine the properties of transition states for reactions involving proteins. Comparing the effect of amino acid replacements on kinetics and thermodynamics of a reaction identifies the interactions that are important for the rate-limiting step of a process. This method has been successfully applied to characterize transition states for protein folding (1, 2), for proteinprotein interactions (3-5) and for conformational changes in folded proteins (6). Protein folding transition states were shown to have native-like topology in the whole protein or in major parts of the structure (7-9) and it is commonly assumed that this includes the presence of native-like secondary structure (10, 11). Because site-directed mutagenesis can only modify amino acid side chains, it is still unclear at which stage of a folding reaction backbone hydrogen bonds in secondary structure elements are formed. Several approaches have been applied to test for secondary structure in protein folding transition states. Replacing amino acids by glycyl and prolyl residues leads to changes in backbone conformation, which was used to probe α-helix formation (12), but these replacements introduce additional effects due to altered side-chain interactions. Introducing ester bonds into the polypeptide backbone (13) also has multiple effects because it leads to the loss of a backbone hydrogen bonding donor and strongly increases conformational flexibility of the polypeptide backbone. Deuteration of a...

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“…This wavelength is easily accessible for femtosecond lasers (since it is obtained by tripling the Ti:S laser wavelength), and S-O substitution may be done site-selectively. Furthermore, it has been shown that incorporation of a thioamide linkage results in only minor changes of the secondary structure of a peptide [83,84] and that secondary structure is indeed changing upon illumination of thiopeptides [85,86]. A recent combined theoretical-experimental femtosecond studies on the photoswitch itself (CH 3 -CSNH-CH 3 ) shows that the isomerization quantum yield is high (30-40%), that the molecule is stable against photodegeneration, and that the isomerization proceeds through two reaction channels, one ultrafast with a <5 ps time constant and one slower with a 200 ps time constant [87].…”

Section: Vibrational Spectroscopy Of Non-equilibrium Dynamics Of Peptmentioning

confidence: 99%

Ultrafast Peptide and Protein Dynamics by Vibrational Spectroscopy

Hamm

2008

Biological and Medical Physics, Biomedical Engineering

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Ultrafast peptide and protein dynamics by vibrational spectroscopyHamm, P Hamm, P (2008). Ultrafast peptide and protein dynamics by vibrational spectroscopy. In: Braun, M; Gilch, P; Zinth, W. Ultrashort laser pulses in biology and medicine. Proteins are molecular machines with a well-defined 3D structure, and it is mainly the success of X-ray and NMR spectroscopic techniques that made the tremendous progress in structural biology happen. However, it is also clear that biomolecular processes generally involve conformational changes of proteins and enzymes. Mostly due to a lack of appropriate spectroscopic tools, much less is known about the dynamics of protein structures. Protein dynamics occurs on a large range of time scales, which can coarsely be related to various length scales: Dynamics of tertiary and quaternary structure extends from milliseconds to seconds and even longer, while formation of secondary structure has been observed between 50 ns and a few microseconds [1][2][3][4][5][6][7][8][9][10][11][12]. Nevertheless, several experiments have provided strong hints for the relevance of even faster processes from the observation of large instantaneous signals, which could not be time-resolved [2,7,13]. For example, Thompson et al.[5] estimated a "zipping time" for a 21-residue α-helix of 300 ps (i.e., the time for closing of subsequent hydrogen bonds, once an initial helix turn is formed), while Huang et al. [7] indirectly concluded that helix nucleation might occur on a subnanosecond time scale. Also molecular dynamics (MD) simulations suggest that peptides and proteins can undergo considerable structural changes within 1 ns or less [8-10, 14, 15]. Hummer et al. [16] found the formation of the first α-helical turn within 0.1-1 ns in work on helix nucleation in short Ala and Gly based peptides. Daura et al. [9,17] simulated equilibrium folding/unfolding of a β-heptapeptide at the melting point and above to obtain statistics on the populations of the folded and unfolded states. Several folding/unfolding events were observed in a 50 ns trajectory, where the actual transitions from unfolded to folded conformations could be as fast as 50-100ps.

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Conformational Stability of Helical Peptides Containing a Thioamide Linkage

Cited by 76 publications

References 19 publications

Coexistence of Hydrogen‐Bonded Loop and Extended Tetrapeptide Conformations

Coexistence of Hydrogen‐Bonded Loop and Extended Tetrapeptide Conformations

Mapping backbone and side-chain interactions in the transition state of a coupled protein folding and binding reaction

Ultrafast Peptide and Protein Dynamics by Vibrational Spectroscopy

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