title: Helix formation and capping energetics of arginine analogs with varying side chain length.
abstract: 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 Agp<Agb<Arg<Agh, showing more favorable C-cap energetics with increasing side chain length. In contrast, helix propensity followed the trend Agp<Agb<Arg>Agh, 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.
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan. rpcheng@ntu.edu.tw
authors.forename: Richard P
authors.initials: RP
authors.lastname: Cheng
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Weng
authors.forename: Wei-Ren
authors.initials: WR
authors.lastname: Wang
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Koyack
authors.forename: Yuta
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Cheng-Hsun
authors.initials: CH
authors.lastname: Wu
authors.forename: Po-An
authors.initials: PA
authors.lastname: Yang
authors.forename: Hao-Chun
authors.initials: HC
authors.lastname: Hsu
authors.forename: Hsiou-Ting
authors.initials: HT
authors.lastname: Kuo
authors.forename: Prashant
authors.initials: P
authors.lastname: Girinath
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Fang
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D010455:Peptides; D001120:Arginine