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Uncovering structural origin relating to non-Markov protein dynamics

Research Project

Project/Area Number 20K03883
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 13040:Biophysics, chemical physics and soft matter physics-related
Research InstitutionOsaka Metropolitan University (2022-2023)
Yokohama City University (2020-2021)

Principal Investigator

Moritsugu Kei  大阪公立大学, 大学院理学研究科, 教授 (80599506)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsタンパク質 / ダイナミクス / 分子動力学シミュレーション / マルコフ状態モデル / 重み付きアンサンブル法 / シニョリン / Pin1 / SARS-CoV-2 3CLプロテアーゼ / ランジュバンモデル / SARS CoV-2 3CLプロテアーゼ / 薬剤結合 / アクチン / マルコフモデル / 機械学習 / リボース結合タンパク質 / 非マルコフ
Outline of Research at the Start

タンパク質の分子機能に関わる折れ畳みや構造変化の時定数を正確に計算するには、ダイナミクスに内在する非マルコフ的な「履歴」が鍵となる。本研究では、タンパク質ダイナミクスの非マルコフ性を定量化し、その構造起因を解明することを目指す。そのため、非マルコフ的に構造変化するパスを重み付きアンサンブル法といった効率的な分子動力学シミュレーション手法により生成し、状態を定義した上で構造に履歴ラベルを付加、更に、遷移構造におけるラベルの違いを有意に説明する構造的特徴量を機械学習の手法により抽出する、という包括的方法論を構築する。

Outline of Final Research Achievements

Markov state model has been used to describe the biomolecular dynamics, but the underlying Markovian assumption is still problematic for such complicated motions. In this study, we aimed at quantitatively analyzing such non-Markov contribution hidden in the dynamics and revealing its structural origin. To do this, we firstly studied the chignolin dynamics as a simplest model by directly simulating the folding events and constructed the dynamics models such as history-dependent Markov model and Langevin model. Secondly, we developed the simulation method, weighted ensemble, to generate the structural change paths that were not based on Markovian assumption, and applied the method to the isomerization of the substrate peptide via Pin1, a typical proline isomerization enzyme, and to the direct simulations of the substrate peptide association and dissociation on SARS-CoV-2 3CL protease.

Academic Significance and Societal Importance of the Research Achievements

タンパク質やDNAといった生体分子の運動は極めて複雑であるが、そのなかで例えば構造変化しシグナルを下流に伝えるといった分子機能を細胞内で発現する。つまり、立体構造情報に基づいて物理・化学的に合理的な原子レベルのモデルによって得られる機能発現過程の全体像から、認識の特異性決定因子の同定、アミノ酸変異の影響の理解などといった、それぞれの系の課題である薬剤設計、疾病の理解につながる情報を提供することができる。本研究では、そのようなダイナミクスの理解に直結する運動モデルの構築、更に、それを計算機上で再現する新規シミュレーション手法の開発に取り組んだ。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (14 results)

All 2024 2023 2022 2021 2020

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 3 results) Presentation (7 results) (of which Invited: 3 results)

  • [Journal Article] A cutoff-based method with charge-distribution-data driven pair potentials for efficiently estimating electrostatic interactions in molecular systems.2023

    • Author(s)
      Ikuo Fukuda, Kei Moritsugu, Junichi Higo, Yoshifumi Fukunishi.
    • Journal Title

      J. Chem. Phys.

      Volume: 159 Issue: 23 Pages: 234116-234116

    • DOI

      10.1063/5.0172270

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Binding and Unbinding Pathways of Peptide Substrates on the SARS-CoV-2 3CL Protease2022

    • Author(s)
      Moritsugu Kei、Ekimoto Toru、Ikeguchi Mitsunori、Kidera Akinori
    • Journal Title

      Journal of Chemical Information and Modeling

      Volume: 63 Issue: 1 Pages: 240-250

    • DOI

      10.1021/acs.jcim.2c00946

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Structures and mechanisms of actin ATP hydrolysis2022

    • Author(s)
      Kanematsu Yusuke、Narita Akihiro、Oda Toshiro、Koike Ryotaro、Ota Motonori、Takano Yu、Moritsugu Kei、Fujiwara Ikuko、Tanaka Kotaro、Komatsu Hideyuki、Nagae Takayuki、Watanabe Nobuhisa、Iwasa Mitsusada、Ma?da Yuichiro、Takeda Shuichi
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 119 Issue: 43

    • DOI

      10.1073/pnas.2122641119

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Allosteric Regulation of 3CL Protease of SARS-CoV-2 and SARS-CoV Observed in the Crystal Structure Ensemble2021

    • Author(s)
      Kidera Akinori、Moritsugu Kei、Ekimoto Toru、Ikeguchi Mitsunori
    • Journal Title

      Journal of Molecular Biology

      Volume: 433 Issue: 24 Pages: 167324-167324

    • DOI

      10.1016/j.jmb.2021.167324

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multiscale Enhanced Sampling Using Machine Learning2021

    • Author(s)
      Moritsugu Kei
    • Journal Title

      Life

      Volume: 11 Issue: 10 Pages: 1076-1076

    • DOI

      10.3390/life11101076

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [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 Research-status Report
    • Peer Reviewed
  • [Journal Article] Flexibility and cell permeability of cyclic Ras-inhibitor peptides revealed by coupled Nose Hoover equation2021

    • Author(s)
      Kei Moritsugu, Koh Takeuchi, Narutoshi Kamiya, Junichi Higo, Isao Yasumatsu, Yoshifumi Fukunishi and Ikuo Fukuda
    • Journal Title

      Journal of Chemical Information and Modeling

      Volume: 61 Issue: 4 Pages: 1921-1930

    • DOI

      10.1021/acs.jcim.0c01427

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] 生体分子に向けたシミュレーション法の開発とその応用研究2024

    • Author(s)
      森次 圭
    • Organizer
      スーパーコンピュータワークショップ2023
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 重み付きアンサンブル法によるプロテアーゼへの基質結合・解離シミュレーション2024

    • Author(s)
      森次 圭
    • Organizer
      第3 回 構造基盤創薬化学研究会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 重み付きアンサンブル法と生体分子への応用2022

    • Author(s)
      森次 圭
    • Organizer
      第3回生体分子シミュレーション・モデリング研究会
    • Related Report
      2022 Research-status Report
  • [Presentation] Enhanced sampling methods targeting at large proteins2021

    • Author(s)
      Kei Moritsugu
    • Organizer
      第59回日本生物物理学会年会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] VAE-driven multiscale enhanced sampling2021

    • Author(s)
      Kei Moritsugu
    • Organizer
      第59回日本生物物理学会年会
    • Related Report
      2021 Research-status Report
  • [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
      第58回日本生物物理学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] Enhanced conformational sampling of cyclic peptide Cyclorasin by coupled Nose-Hoover equation2020

    • Author(s)
      森次 圭
    • Organizer
      情報計算科学生物学会2020年大会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2025-01-30  

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