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Searching the bottleneck of enzymatic reactions: Reaction path sampling calculation accompanied with experiment

Research Project

Project/Area Number 17KT0101
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section特設分野
Research Field Transition State Control
Research InstitutionNippon Medical School

Principal Investigator

Fujisaki Hiroshi  日本医科大学, 医学部, 教授 (60573243)

Co-Investigator(Kenkyū-buntansha) 楯 真一  広島大学, 統合生命科学研究科(理), 教授 (20216998)
山本 典史  千葉工業大学, 工学部, 准教授 (30452163)
森次 圭  横浜市立大学, 生命医科学研究科, 特任准教授 (80599506)
Project Period (FY) 2017-07-18 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Keywords酵素反応 / 生体分子シミュレーション / レアイベント / パスサンプリング / 反応経路 / 遷移状態 / キネティクス / 自由エネルギー障壁 / 重み付きアンサンブル法 / 生体物質の物理
Outline of Final Research Achievements

A novel molecular simulation method called the weighted ensemble method was used to study the dynamics of enzymatic reactions near the transition state, which is one of the functions of biomolecules such as DNA, proteins, and peptides. The weighted ensemble method uses massively parallel computations to run multiple weighted particles to dynamically and efficiently calculate rare events such as structural changes associated with enzymatic reactions. The method was applied to the folding of small peptides, the isomerization of substrates by the PIN1 enzyme, and the conformational change of adenylate kinase to dynamically characterize the time scales and transition states along the reaction path.

Academic Significance and Societal Importance of the Research Achievements

酵素反応における遷移状態付近の情報は、その反応を直接支配するので非常に重要であるが、その生起する時間は(人間のスケールでは)非常に短く、また遷移状態のエネルギーが高い場合は非常に稀におこる現象(レアイベント)となる。それを実験的にも計算的にも捉えることは難しいが、ここではパスサンプリングの手法の一つである、重み付きアンサンブル法を生体分子シミュレーションとして実装し、遷移状態付近でどのように分子の配置が動的に変化していくかを直接捉えることができた。これは生化学における重要な知見を与えるのみならず、タンパク質の構造変化やリガンド結合などのダイナミクスを計算的に理解する上でも重要な方法論たりうる。

Report

(5 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (35 results)

All 2021 2020 2019 2018 2017

All Journal Article (7 results) (of which Peer Reviewed: 6 results,  Open Access: 3 results) Presentation (28 results) (of which Int'l Joint Research: 10 results,  Invited: 6 results)

  • [Journal Article] Path ensembles for Pin1-catalyzed cis-trans isomerization of a substrate calculated by weighted ensemble simulations2021

    • Author(s)
      Kei Moritsugu, Norifumi Yamamoto, Yasushige Yonezawa, Shin-ichi Tate, and Hiroshi Fujisaki
    • Journal Title

      Journal of Chemical Theory and Computation

      Volume: 17 Issue: 4 Pages: 2522-2529

    • DOI

      10.1021/acs.jctc.0c01280

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Weighted ensemble simulations for conformational changes of proteins2021

    • Author(s)
      Fujisaki Hiroshi、Matsunaga Yasuhiro、Moritsugu Kei
    • Journal Title

      AIP Conference Proceedings

      Volume: 2343 Pages: 020016-020016

    • DOI

      10.1063/5.0047730

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mathematical model for wound healing caused by exogeneous mechanical forces2021

    • Author(s)
      Odagiri Kenta、Fujisaki Hiroshi
    • Journal Title

      AIP Conference Proceedings

      Volume: 2543 Pages: 020017-020017

    • DOI

      10.1063/5.0048360

    • NAID

      130007508572

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Conformational change of a biomolecule studied by the weighted ensemble method: Use of the diffusion map method to extract reaction coordinates2018

    • Author(s)
      Fujisaki Hiroshi、Moritsugu Kei、Mitsutake Ayori、Suetani Hiromichi
    • Journal Title

      The Journal of Chemical Physics

      Volume: 149 Issue: 13 Pages: 134112-134112

    • DOI

      10.1063/1.5049420

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Exploring Configuration Space and Path Space of Biomolecules Using Enhanced Sampling Techniques?Searching for Mechanism and Kinetics of Biomolecular Functions2018

    • Author(s)
      Fujisaki Hiroshi、Moritsugu Kei、Matsunaga Yasuhiro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 19 Issue: 10 Pages: 3177-3177

    • DOI

      10.3390/ijms19103177

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Energetics and Conformational Pathways of Functional Rotation in the Multidrug Transporter AcrB2018

    • Author(s)
      Y. Matsunaga, T. Yamane, T. Terada, K. Moritsugu, H. Fujisaki, S. Murakami, M. Ikeguchi, A. Kidera
    • Journal Title

      eLife

      Volume: 7 Pages: 1-19

    • DOI

      10.7554/elife.31715

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 生体分子におけるレアイベントサンプリング: Onsager-Machlup 作用を用いた計算手法2017

    • Author(s)
      藤崎弘士
    • Journal Title

      京都大学数理解析研究所講究録

      Volume: 2028 Pages: 38-48

    • Related Report
      2017 Research-status Report
    • Open Access
  • [Presentation] Weighted ensemble simulations for conformational changes of proteins2020

    • Author(s)
      Hiroshi Fujisaki
    • Organizer
      16th Int. Conf. Computational Methods in Sciences and Engineering
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 構造変化とリガンド結合の競合ダイナミクス:重み付き アンサンブル法を用いた計算2020

    • Author(s)
      藤崎弘士 , 森次圭 , 松永康佑
    • Organizer
      日本物理学会 2020 年 秋季大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 細胞に加わる力を考慮した血管ネットワーク形成のモデル化2020

    • Author(s)
      小田切健太 藤崎弘士
    • Organizer
      日本物理学会 2020 年 秋季大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Diffusion map analysis of long time protein dynamics,2020

    • Author(s)
      Hiroshi Fujisaki, Hiroto Kikuchi , Hiromichi Suetani, Ayori Mitsutake
    • Organizer
      第 58 回日本生物物理学会年会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Obtaining path ensemble of Pin1 catalyzed cis-trans isomerization by weighted ensemble simulation2020

    • Author(s)
      Kei Moritsugu, Norifumi Yamamoto, Yasushige Yonezawa, Shin ichi Tate, Hiroshi Fujisaki
    • Organizer
      第 58 回日本生物物理学会年会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 重み付きアンサンブル法によるPin1異性化のパスサンプリング2020

    • Author(s)
      森次圭, 山本典史, 米澤康滋, 楯真一, 藤崎弘士
    • Organizer
      日本物理学会 第75回年次大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 細胞に加わる力を考慮した創傷治癒過程のモデル化2020

    • Author(s)
      小田切健太、藤崎弘士
    • Organizer
      日本物理学会 第75回年次大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Weighted ensemble simulations of biomolecules2019

    • Author(s)
      Hiroshi Fujisaki
    • Organizer
      Workshop: Data analysis and machine learning in dynamical systems
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 生体分子の構造変化経路サンプリング2019

    • Author(s)
      藤崎弘士
    • Organizer
      第12回分子シミュレーションスクール---基礎から応用まで---
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 重み付きアンサンブル法を用いたタンパク質の構造変化とキネティックスの計算2019

    • Author(s)
      藤崎弘士, 森次圭, 松永康佑
    • Organizer
      日本物理学会
    • Related Report
      2019 Research-status Report
  • [Presentation] 分子動力学を用いたアセチルベンゾニトリルからクロロフォルム溶媒へのエネルギー移動の計算2019

    • Author(s)
      菊地浩人, 藤崎弘士
    • Organizer
      日本物理学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Weighted ensemble simulation of the cis-trans isomerization in Pin1 enyzme using the QM/MM method2019

    • Author(s)
      N. Yamamoto, K. Moritsugu, Y. Yonezawa, S. Tate, H. Fujisaki
    • Organizer
      日本生物物理学会
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Applications of a diffusion map method to protein dynamics2019

    • Author(s)
      H. Kikuchi, A. Mitsutake, H. Fujisaki
    • Organizer
      日本生物物理学会
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 重み付きアンサンブル法による生体分子の構造変化ダイナミクスの計算2019

    • Author(s)
      藤崎弘士,森次圭,松永康佑
    • Organizer
      第33回分子シミュレーション学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Weighted ensemble simulations of biomolecules: Applications to peptides and proteins2019

    • Author(s)
      H. Fujisaki
    • Organizer
      APS March Meeting 2019
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Weighted ensemble simulations of biomolecules2018

    • Author(s)
      H. Fujisaki, K. Moritsugu, A. Mitsutake, Y. Matsunaga, H. Suetani
    • Organizer
      11th European Conference on Mathematical and Theoretical Biology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Mathematical model for wound healing caused by exogeneous mechanical forces2018

    • Author(s)
      K. Odagiri, H. Fujisaki
    • Organizer
      11th European Conference on Mathematical and Theoretical Biology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Applications of manifold learning techniques to protein dynamics2018

    • Author(s)
      H. Kikuchi, H. Fujisaki
    • Organizer
      56th Annual Meeting of the Biophysical Society of Japan
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Weighted ensemble simulations of biomolecules2018

    • Author(s)
      Hiroshi Fujisaki
    • Organizer
      56th Annual Meeting of the Biophysical Society of Japan
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] プロリン異性化酵素の重み付きアンサンブル法による計算とその加速2018

    • Author(s)
      藤崎弘士,森次圭,米澤康滋,楯真一
    • Organizer
      日本物理学会2018年秋季大会
    • Related Report
      2018 Research-status Report
  • [Presentation] 溶液中のアセチルベンゾニトリルにおけるエネルギー移動:非平衡MDによる計算2018

    • Author(s)
      菊地浩人,藤崎弘士
    • Organizer
      日本物理学会2018年秋季大会
    • Related Report
      2018 Research-status Report
  • [Presentation] 重み付きアンサンブル法によるタンパク質ダイナミクスの計算2018

    • Author(s)
      藤崎弘士
    • Organizer
      大阪大学蛋白質研究所セミナー「生体分子内情報伝達機構の新展開」
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Combining weighted ensemble method with Lyapunov weighted dynamics: Application to proteins2018

    • Author(s)
      H. Fujisaki, K. Moritsugu, Y. Matsunaga, H. Suetani
    • Organizer
      Biophysical Society Meeting 62nd Annual Meeting (San Francisco)
    • Related Report
      2017 Research-status Report
  • [Presentation] 複雑な分子はどんな道筋を通って、どれくらい速く反応するのか? -生体分子の構造変化とレアイベント-2017

    • Author(s)
      藤崎弘士
    • Organizer
      大分大学 自然科学セミナー
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 生体分子の構造変化経路サンプリング2017

    • Author(s)
      藤崎弘士
    • Organizer
      第11回分子シミュレーションスクール--- 基礎から応用まで---
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 重み付きアンサンブル法を用いたタンパク質のパスサンプリング2017

    • Author(s)
      藤崎弘士,森次圭,末谷大道
    • Organizer
      日本物理学会秋季大会(岩手大学)
    • Related Report
      2017 Research-status Report
  • [Presentation] 機械的刺激の効果を考慮した創傷治癒の数理モデル2017

    • Author(s)
      小田切健太、藤崎弘士
    • Organizer
      日本物理学会秋季大会(岩手大学)
    • Related Report
      2017 Research-status Report
  • [Presentation] PIN1 酵素における異性化反応への重み付きアンサンブル法の適用2017

    • Author(s)
      藤崎弘士,森次圭,米澤康滋,楯真一
    • Organizer
      分子シミュレーション討論会(金沢商工会議所)
    • Related Report
      2017 Research-status Report

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Published: 2017-07-21   Modified: 2022-01-27  

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