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

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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.

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Acknowledgments

This work was supported by NYSTAR James D. Watson Investigator Program (R.P.C.), Kapoor funds (R.P.C.), The State University of New York at Buffalo (R.P.C.), National Science Foundation (R.P.C., CHE0809633), National Taiwan University (R.P.C.), National Science Council (R.P.C., NSC-97-2113-M-002-019-MY2, NSC-98-2119-M-002-025, NSC-99-2113-M-002-002-MY2; Y.J.W., NSC-98-2815-C-002-056-M). The authors would like to thank the Computer and Information Networking Center at National Taiwan University for the support of the high-performance computing facilities. The authors would like to thank Professor Cheu-Pyeng Cheng (Department of Chemistry, National Tsing Hua University) for helpful discussions, and Ms. Chia-Wen Kuo for proofreading the manuscript.

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  1. Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan

    Richard P. Cheng, Yi-Jen Weng, Wei-Ren Wang, Cheng-Hsun Wu, Po-An Yang, Hao-Chun Hsu, Hsiou-Ting Kuo & Chun-Jen Fang

  2. Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260-3000, USA

    Marc J. Koyack, Yuta Suzuki & Prashant Girinath

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  1. Richard P. Cheng
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Correspondence to Richard P. Cheng.

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Cheng, R.P., Weng, YJ., Wang, WR. et al. Helix formation and capping energetics of arginine analogs with varying side chain length. Amino Acids 43, 195–206 (2012). https://doi.org/10.1007/s00726-011-1064-2

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