A new interpretation of the structure and solvent dependence of the far UV circular dichroism spectrum of short oligopeptides

Kumar, Anshuman; Schweitzer‐Stenner, Reinhard; Wong, Bryan M.

doi:10.1039/c9cc01513b

Cited by 18 publications

(28 citation statements)

References 23 publications

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“…Even though RADA16-I was in disordered conformation, noncovalent forces such as hydrophobic interaction and electrostatic interaction could drive the fibrillization behavior, and during this fibrillization process, the peptide could be pressed into an ordered β-sheet. Except for our experimental findings reported in this work, some earlier computational studies have also suggested that β-strand conformation could rise as a result of water-mediated peptide folding. , These results reevaluated the importance of typical β-strand for peptide fibrillization, providing a deeper insight into the general mechanism of peptide self-assembly. More detailed information in the disordered secondary structure could be further exploited, for example, by analyzing the peptide sequence in detail. , This would be important for further clarifying how such disordered peptide monomers support fibrillization.…”

Section: Discussionsupporting

confidence: 64%

“…Except for our experimental findings reported in this work, some earlier computational studies have also suggested that β-strand conformation could rise as a result of water-mediated peptide folding. 33,34 These results reevaluated the importance of typical β-strand for peptide fibrillization, providing a deeper insight into the general mechanism of peptide self-assembly. More detailed information in the disordered secondary structure could be further exploited, for example, by analyzing the peptide sequence in detail.…”

Section: ■ Conclusionmentioning

confidence: 85%

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Alternative Causal Link between Peptide Fibrillization and β-Strand Conformation

2021

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In the prevailing phenomenon of peptide fibrillization, β-strand conformation has long been believed to be an important structural basis for peptide assembly. According to a widely accepted theory, in most peptide fibrillization processes, peptide monomers need to intrinsically take or transform to β-strand conformation before they can undergo ordered packing to form nanofibers. In this study, we reported our findings on an alternative peptide fibrillization pathway starting from a disordered secondary structure, which could then transform to β-strand after fibrillization. By using circular dichroism, thioflavin-T binding test, and transmission electron microscopy, we studied the secondary structure and assembly behavior of Ac-RADARADARADARADA-NH 2 (RADA16-I) in a low concentration range. The effects of peptide concentration, solvent polarity, pH, and temperature were investigated in detail. Our results showed that at very low concentrations, even though the peptide was in a disordered secondary structure, it could still form nanofibers through intermolecular assembly, and under higher peptide concentrations, the transformation from the disordered structure to β-strand could happen with the growth of nanofibers. Our results indicated that even without ordered β-strand conformation, driving forces such as hydrophobic interaction and electrostatic interaction could still play a determinative role in the self-assembly of peptides. At least in some cases, the formation of β-strand might be the consequence rather than the cause of peptide fibrillization.

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Section: Discussionsupporting

confidence: 64%

Section: ■ Conclusionmentioning

confidence: 85%

Alternative Causal Link between Peptide Fibrillization and β-Strand Conformation

2021

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“…Circular dichroism (CD) spectroscopy is increasingly recognized as very sensitive indicator of protein conformation, relying on a plethora of electronic transitions. The FUV‐ECD spectra of Trp‐cage proteins (e.g., Exenatide, E19, E19_SS) are typically the weighted sums of the C‐ (folded and highly helical) and U‐type (unfolded) base curves (Figure A), as assigned and verified by means of NMR spectroscopy .…”

Section: Resultsmentioning

confidence: 99%

Compactness of Protein Folds Alters Disulfide‐Bond Reducibility by Three Orders of Magnitude: A Comprehensive Kinetic Case Study on the Reduction of Differently Sized Tryptophan Cage Model Proteins

et al. 2019

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A new approach to monitor disulfide‐bond reduction in the vicinity of aromatic cluster(s) has been derived by using the near‐UV range (λ=266–293 nm) of electronic circular dichroism (ECD) spectra. By combining the results from NMR and ECD spectroscopy, the 3D fold characteristics and associated reduction rate constants (k) of E19_SS, which is a highly thermostable, disulfide‐bond reinforced 39‐amino acid long exenatide mimetic, and its N‐terminally truncated derivatives have been determined under different experimental conditions. Single disulfide bond reduction of the E19_SS model (with an 18‐fold excess of tris(2‐carboxyethyl)phosphine, pH 7, 37 °C) takes hours, which is 20–30 times longer than that expected, and thus, would not reach completion by applying commonly used reduction protocols. It is found that structural, steric, and electrostatic factors influence the reduction rate, resulting in orders of magnitude differences in reduction half‐lives (900>t1/2>1 min) even for structurally similar, well‐folded derivatives of a small model protein.

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“…Due to the conformational restriction of the N-methyl group and isoindolone fragment, only a few stable low energy conformers for each configuration were found (as shown in Table S1). The obtained molecules were directly optimized with B3LYP/6-31G (d, p) and the CD spectra were simulated at the ωB97XD/cc-pVDZ level based on the time-dependent density functional theory method (TDDFT) [17,18]. The AC of C-3 position can be distinguished when the simulated spectrum of a selected configuration is consistent with the experimental one.…”

Section: Determination Of Absolute Configurations (Acs)mentioning

confidence: 99%

Photoinduced Synthesis of Methylated Marine Cyclopeptide Galaxamide Analogs with Isoindolinone as Anticancer Agents

et al. 2022

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The methylation of amino acid residues has played an important role in the biological function of bioactive peptides. In this paper, various methyl-modified and stereostructural-modified marine cyclopeptide galaxamide analogs with isoindolinone were synthesized by a photoinduced single electron transfer cyclization reaction. It was found that the single-methyl substitution was beneficial for the bioactivity of cyclic analogs with isoindolinone fragments, and the influence of methylation on bioactivity is uncertain and is sometimes case-specific. The compound with a single methyl group at Gly5 (compound 8) showed the strongest antiproliferative activity against HepG-2 cells. The tumor cell apoptosis, cell cycle, mitochondrial membrane potential, intracellular Ca2+ concentration and lactate dehydrogenase activity have been studied extensively to evaluate the antitumor potential of compound 8. Western blotting tests showed that compound 8 could decrease the MDM2 level and increase p53 levels efficiently. Careful molecular docking suggested that cyclic peptide 8 could bind firmly with MDM2 oncoprotein, indicating that MDM2 may be a potential drug target of the prepared peptides.

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A new interpretation of the structure and solvent dependence of the far UV circular dichroism spectrum of short oligopeptides

Abstract: Classical excitonic models are unsuitable for describing the electronic structure of polypeptides, and explicit consideration of water is essential.

Cited by 18 publications

References 23 publications

Alternative Causal Link between Peptide Fibrillization and β-Strand Conformation

Alternative Causal Link between Peptide Fibrillization and β-Strand Conformation

Compactness of Protein Folds Alters Disulfide‐Bond Reducibility by Three Orders of Magnitude: A Comprehensive Kinetic Case Study on the Reduction of Differently Sized Tryptophan Cage Model Proteins

Photoinduced Synthesis of Methylated Marine Cyclopeptide Galaxamide Analogs with Isoindolinone as Anticancer Agents

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