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Development of SAAP3D force field and the application to replica-exchange Monte Carlo simulation for chignolin and C-peptide

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Abstract

Single amino acid potential (SAAP) would be a prominent factor to determine peptide conformations. To prove this hypothesis, we previously developed SAAP force field for molecular simulation of polypeptides. In this study, the force field was renovated to SAAP3D force field by applying more accurate three-dimensional main-chain parameters, instead of the original two-dimensional ones, for the amino acids having a long side-chain. To demonstrate effectiveness of the SAAP3D force field, replica-exchange Monte Carlo (REMC) simulation was performed for two benchmark short peptides, chignolin (H-GYDPETGTWG-OH) and C-peptide (CHO-AETAAAKFLRAHA-NH2). For chignolin, REMC/SAAP3D simulation correctly produced native β-turn structures, whose minimal all-atom root-mean-square deviation value measured from the native NMR structure (except for H) was 1.2 Å, at 300 K in implicit water, along with misfolded β-hairpin structures with unpacked aromatic side chains of Tyr2 and Trp9. Similar results were obtained for chignolin analog [G1Y,G10Y], which folded more tightly to the native β-turn structure than chignolin did. For C-peptide, on the other hand, the α-helix content was larger than the β content on average, suggesting a significant helix-forming propensity. When the imidazole side chain of His12 was protonated (i.e., [His12Hip]), the α content became larger. These observations as well as the representative structures obtained by clustering analysis were in reasonable agreement not only with the structures of C-peptide that were determined in this study by NMR in 30% CD3CD in H2O at 298 K but also with the experimental and theoretical behaviors having been reported for protonated C-peptide. Thus, accuracy of the SAAP force field was improved by applying three-dimensional main-chain parameters, supporting prominent importance of SAAP for peptide conformations.

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Acknowledgements

We thank R. Ooka (Tokai University) for assistance of the synthesis of C-peptide. This work was supported by Grant-in-Aid for Scientific Research on Innovative Areas (No. 2120005) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Author notes

  1. Hiroyuki Onuki

    Present address: Tokyo Chemical Industry Co., Ltd. Toshima, Kita, Tokyo, 114-0003, Japan

  2. Hiroshi Hirota

    Present address: Chemical Genomics Research Group, RIKEN CSRS, Wako, Saitama, 351-0198, Japan

Authors and Affiliations

  1. Department of Chemistry, School of Science, Tokai University, Kitakaname, Hiratsuka, Kanagawa, 259-1292, Japan

    Michio Iwaoka, Toshiki Suzuki, Yuya Shoji, Kenichi Dedachi & Taku Shimosato

  2. Laboratory of General Education for Science and Technology, School of Science, Tokai University, Kitakaname, Hiratsuka, Kanagawa, 259-1292, Japan

    Toshiya Minezaki

  3. Institute for Protein Research, Osaka University, Yamadaoka, Suita, Osaka, 565-0871, Japan

    Hironobu Hojo

  4. Genomic Sciences Center, RIKEN, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan

    Hiroyuki Onuki & Hiroshi Hirota

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  1. Michio Iwaoka
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Iwaoka, M., Suzuki, T., Shoji, Y. et al. Development of SAAP3D force field and the application to replica-exchange Monte Carlo simulation for chignolin and C-peptide. J Comput Aided Mol Des 31, 1039–1052 (2017). https://doi.org/10.1007/s10822-017-0084-8

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