Positional Effects on Helical Ala-Based Peptides

Cheng, Richard P.; Girinath, Prashant; Suzuki, Yuta; Kuo, Hsiou Ting; Hsu, Hsien‐Wen; Wang, Wei Ren; Yang, Po An; Gullickson, Donald; Wu, Chang-Chieh; Koyack, Marc J.; Chiu, Hsien Po; Weng, Yi Jen; Hart, Pier; Kokona, Bashkim; Fairman, Robert; Lin, Tzu‐En; Barrett, Olivia J.

doi:10.1021/bi101156j

Cited by 9 publications

(23 citation statements)

References 135 publications

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“…As such, these peptides should not associate in neutral aqueous buffers. Furthermore, analogous peptides have been shown to be monomeric in solution (Padmanabhan et al 1990;Chakrabartty et al 1994;Doig and Baldwin 1995;Chiu et al 2006;Chiu and Cheng 2007;Cheng et al 2010), and the CD spectrum of each peptide did not alter significantly between 80 and 160 lM. Therefore, the peptides are most likely monomeric in solution, and intermolecular interactions should not contribute significantly to the helical content of these peptides in solution.…”

Section: Synthesis Of Protected Arg Analogsmentioning

confidence: 92%

“…The Ala-based peptides were designed according to analogous peptides initially studied by Baldwin Doig and Baldwin 1995) and later by our group (Chiu et al 2006;Cheng et al 2010) (Table 1). To investigate the effect of the Arg side chain length on helix propensity (w), four XaaAla peptides were designed with four positions substituted simultaneously with the same Arg analog .…”

Section: Synthesis Of Protected Arg Analogsmentioning

confidence: 99%

“…The four NXaa01 peptides and the four CXaa19 peptides (each with one Arg analog at the N-terminus and C-terminus, respectively) were designed to derive the N-cap (n) and C-cap (c) parameters for the Arg analogs, respectively (Doig and Baldwin 1995). The N-terminus of all peptides was acetylated and the C-terminus was designed to be a carboxyamide so there would be no bias (from charged termini) on the statistical mechanical capping parameters derived for the Arg analogs (Cheng et al 2010). Based on the modified Lifson-Roig theory (Lifson and Roig 1961;Doig et al 1994;Chakrabartty et al 1994;Doig and Baldwin 1995;Chiu et al 2006;Cheng et al 2010), the probability of residue Xaa for all conformational states in NXaa01 peptides would be represented by only v (initiation parameter), n (N-cap parameter), and 1 (the probability for random coil surrounded by residues in random coil conformation).…”

Section: Synthesis Of Protected Arg Analogsmentioning

confidence: 99%

“…The helix formation parameters including N-cap (n), C-cap (c), and helix propensity (w) were derived from the CD data using modified Lifson-Roig theory (Lifson and Roig 1961;Doig et al 1994;Chakrabartty et al 1994;Doig and Baldwin 1995;Chiu et al 2006;Cheng et al 2010) ( Table 3). The corresponding free energies were also derived ( Table 3).…”

Section: Helix Formation Parameters For Arg Analogsmentioning

confidence: 99%

“…Therefore, thorough studies on the structural effect of incorporating Arg analogs would serve as the foundation to facilitate the use of these analogs in various applications. Since one-third of protein residues adopt a helical conformation (Chou and Fasman 1974;Barlow and Thornton 1988;Cheng et al 2010), herein we report the effect of Arg side chain length on helix formation and capping. We incorporated Arg analogs with varying side chain lengths into 19-residue peptides using Fmoc-based chemistry.…”

Section: Introductionmentioning

confidence: 99%

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Helix formation and capping energetics of arginine analogs with varying side chain length

et al. 2011

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Arginine (Arg) has been used for recognizing negatively charged biological molecules, cell penetration, and oligosaccharide mass signal enhancement. The versatility of Arg has inspired the need to develop Arg analogs and to research the structural effects of incorporating Arg analogs. Accordingly, we investigated the effect of Arg side chain length on helix formation by studying 12 Ala-based peptides containing the Arg analogs (S)-2-amino-6-guanidino-hexanoic acid (Agh), (S)-2-amino-4-guanidinobutyric acid (Agb), and (S)-2-amino-3-guanidinopropionic acid (Agp). Solid phase guanidinylation with orthogonal protection strategies was necessary to synthesize Agb- and Agp-containing peptides using Fmoc-based chemistry. The fraction helix for the peptides was determined by circular dichroism spectroscopy, and used to derive the statistical mechanical parameters and energetics for N-capping, C-capping, and helix propagation (propensity). All four Arg analogs were unfavorable for N-capping. The C-cap parameter followed the trend AgpAgh, highlighting the uniqueness of the Arg side chain length in helix formation. Molecular mechanics calculations and a survey on protein structures were consistent with the experimental results. Furthermore, calculations and survey both showed that the g- conformation for the χ1 dihedral was present for the first two residues at the N-terminus of helices, but not favored in the center or C-terminus of helices due to sterics. These results should serve as the foundation for developing Arg-related bioactive compounds and technologies.

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Section: Synthesis Of Protected Arg Analogsmentioning

confidence: 92%

Section: Synthesis Of Protected Arg Analogsmentioning

confidence: 99%

Section: Synthesis Of Protected Arg Analogsmentioning

confidence: 99%

Section: Helix Formation Parameters For Arg Analogsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Helix formation and capping energetics of arginine analogs with varying side chain length

et al. 2011

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Effects of Arginine Deimination and Citrulline Side‐Chain Length on Peptide Secondary Structure Formation

Chen

et al. 2019

ChemBioChem

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Post‐translational modifications expand the chemical functionality of peptides and proteins beyond that originating from the encoded amino acids, but studies on the structural effects of these modifications have been limited. Arginine undergoes deimination to give citrulline (Cit), converting the positively charged guanidinium moiety into a neutral urea group. Herein, we report the effect of Arg deimination on secondary structure formation. To understand the reason for the number of methylene units in Cit, the effect of Cit side‐chain length on secondary structure formation was also studied. Ala‐based peptides and β‐hairpin peptides were used to study α‐helix and β‐sheet formation, respectively. Peptides containing Cit analogues were prepared by an orthogonal protecting group strategy coupled with solid‐phase carbamylation. The CD data for the Ala‐based peptides were analyzed by using modified Lifson–Roig theory, showing that the helix propensity of Arg decreased upon deimination and that either shortening or lengthening Cit also decreased the helix propensity. The β‐hairpin peptides were analyzed by NMR methods, showing minimal change in strand formation energetics upon Arg deimination. Altering the Cit side‐chain length did not affect strand formation energetics either. These results should be useful for the preparation of urea‐bearing systems and the design of peptides incorporating urea‐bearing residues with varying side‐chain length.

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Effect of side chain length on intrahelical interactions between carboxylate- and guanidinium-containing amino acids

et al. 2014

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The charge-containing hydrophilic functionalities of encoded charged amino acids are linked to the backbone via different numbers of hydrophobic methylenes, despite the apparent electrostatic nature of protein ion pairing interactions. To investigate the effect of side chain length of guanidinium- and carboxylate-containing residues on ion pairing interactions, α-helical peptides containing Zbb-Xaa (i, i + 3), (i, i + 4) and (i, i + 5) (Zbb = carboxylate-containing residues Aad, Glu, Asp in decreasing length; Xaa = guanidinium residues Agh, Arg, Agb, Agp in decreasing length) sequence patterns were studied by circular dichroism spectroscopy (CD). The helicity of Aad- and Glu-containing peptides was similar and mostly pH independent, whereas the helicity of Asp-containing peptides was mostly pH dependent. Furthermore, the Arg-containing peptides consistently exhibited higher helicity compared to the corresponding Agp-, Agb-, and Agh-containing peptides. Side chain conformational analysis by molecular mechanics calculations showed that the Zbb-Xaa (i, i + 3) and (i, i + 4) interactions mainly involved the χ 1 dihedral combinations (g+, g+) and (g-, g+), respectively. These low energy conformations were also observed in intrahelical Asp-Arg and Glu-Arg salt bridges of natural proteins. Accordingly, Asp and Glu provides variation in helix characteristics associated with Arg, but Aad does not provide features beyond those already delivered by Glu. Importantly, nature may have chosen the side chain length of Arg to support helical conformations through inherent high helix propensity coupled with stabilizing intrahelical ion pairing interactions with the carboxylate-containing residues.

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Positional Effects on Helical Ala-Based Peptides

Cited by 9 publications

References 135 publications

Helix formation and capping energetics of arginine analogs with varying side chain length

Helix formation and capping energetics of arginine analogs with varying side chain length

Effects of Arginine Deimination and Citrulline Side‐Chain Length on Peptide Secondary Structure Formation

Effect of side chain length on intrahelical interactions between carboxylate- and guanidinium-containing amino acids

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