Complementation of molecular movie using analyses of free energy landscape of conformational change, pathway and flux

2021 Fiscal Year Annual Research Report

• Project Area: Non-equilibrium-state molecular movies and their applications
• Project/Area Number: 20H05439
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: 北尾 彰朗 東京工業大学, 生命理工学院, 教授 (30252422)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: アンサンブル / エネルギー地形 / 経路 / 流量 / PaCS-MD/MSM

Outline of Annual Research Achievements

昨年度に引き続き、COVID-19の原因となるSARS-CoV-2ウイルスのエンドヌクレアーゼNsp15を阻害する化合物の探索をおこなった。Nsp15は機能状態で6量体を形成するが、単量体に結合・安定化し、6量体化を阻害する化合物によってNsp15の機能を阻害し、感染能を低下させることを目指したものである。PaCS-MD/MSM法を用いて単量体の自由エネルギー地形を調べ、単量体が最も取りやすい立体構造を明らかにし、これをターゲットとしてバーチャルスクリーニングを行い、有力な化合物を選び出し、dPaCS-MD/MSMによって化合物の標準結合自由エネルギーを評価した結果、非常に強い結合能をもつ化合物を発見することができた。この研究成果について原著論文にまとめ、Scientific Reports誌に掲載した（Inhibition of the hexamerization of SARS-CoV-2 endoribonuclease and modeling of RNA structures bound to the hexamer. DP Tran, Y Taira, T Ogawa, R Misu, Y Miyazawa, A Kitao, Scientific reports 12 (1), 1-15, (2022)）。
また昨年度から引き続いて本領域の名古屋大学清中グループとの共同研究でGタンパク質共役受容体mGlu1とリガンドの相互作用解析を進めた。アミノ酸変異やリガンドのわずかな違いによって生じるmGlu1への効果の違いを評価するためにMD計算によって動的立体構造に生じる違いの評価を進めた。具体的にはFMPTとFPETという2つのリガンドのわずかな違いによってトグルスイッチと呼ばれる部位のダイナミクスに有意な違いが生み出されることを見出した。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] University of Toronto(カナダ)
  • Country Name: CANADA
  • Counterpart Institution: University of Toronto
• [Int'l Joint Research] University of East Anglia(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: University of East Anglia
• [Journal Article] Inhibition of the hexamerization of SARS-CoV-2 endoribonuclease and modeling of RNA structures bound to the hexamer (2022)
  • Author(s): Tran Duy Phuoc、Taira Yuta、Ogawa Takumi、Misu Ryoga、Miyazawa Yoshiki、Kitao Akio
  • Journal Title: Scientific Reports Volume: 12 Pages: 3860(1-15)
  • DOI: 10.1038/s41598-022-07792-2
  • Peer Reviewed / Open Access
• [Journal Article] Dissociation Pathways of the p53 DNA Binding Domain from DNA and Critical Roles of Key Residues Elucidated by dPaCS-MD/MSM (2022)
  • Author(s): Sobeh Mohamed Marzouk、Kitao Akio
  • Journal Title: Journal of Chemical Information and Modeling Volume: 62 Pages: 1294～1307
  • DOI: 10.1021/acs.jcim.1c01508
  • Peer Reviewed
• [Journal Article] Regulatory Switching by Concerted Motions on the Microsecond Time Scale of the Oxygen Sensor Protein FixL (2021)
  • Author(s): Yamawaki Takeo、Mizuno Misao、Ishikawa Haruto、Takemura Kazuhiro、Kitao Akio、Shiro Yoshitsugu、Mizutani Yasuhisa
  • Journal Title: The Journal of Physical Chemistry B Volume: 125 Pages: 6847～6856
  • DOI: 10.1021/acs.jpcb.1c01885
  • Peer Reviewed
• [Journal Article] Using molecular dynamics simulations to prioritize and understand AI-generated cell penetrating peptides (2021)
  • Author(s): Tran Duy Phuoc、Tada Seiichi、Yumoto Akiko、Kitao Akio、Ito Yoshihiro、Uzawa Takanori、Tsuda Koji
  • Journal Title: Scientific Reports Volume: 11 Pages: 107792(1-13)
  • DOI: 10.1038/s41598-021-90245-z
  • Peer Reviewed / Open Access
• [Journal Article] The role of the half-turn in determining structures of Alzheimer’s Aβ wild-type and mutants (2021)
  • Author(s): Hayward Steven、Kitao Akio
  • Journal Title: Journal of Structural Biology Volume: 213 Pages: 107792～107792
  • DOI: 10.1016/j.jsb.2021.107792
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Binding free energy of protein/ligand complexes calculated using dissociation Parallel Cascade Selection Molecular Dynamics and Markov state model (2021)
  • Author(s): Hata Hiroaki、Phuoc Tran Duy、Marzouk Sobeh Mohamed、Kitao Akio
  • Journal Title: Biophysics and Physicobiology Volume: 18 Pages: 305～316
  • DOI: 10.2142/biophysico.bppb-v18.037
  • Peer Reviewed / Open Access
• [Presentation] SARS-CoV-2 エンドリボヌクレアーゼのオリゴマー化阻害 (2021)
  • Author(s): 北尾彰朗
  • Organizer: 新学術領域「高速分子動画」Web セミナー「構造生物学・化学・計算科学を融合させたウイルス・パンデミックに対する取り組み」
  • Invited
• [Presentation] インシリコシミュレーションで探るタンパク質複合体の結合親和性とキネティックス (2021)
  • Author(s): 北尾彰朗
  • Organizer: 日本薬学会構造活性相関部門構造活性フォーラム2021「次期スーパーコンピュータ「富岳」時代の計算創薬」
  • Invited
• [Presentation] Simulated dissociation/association dynamics between proteins and other molecules (2021)
  • Author(s): Akio Kitao
  • Organizer: TSRC WS「Protein Dynamics」
  • Int'l Joint Research / Invited
• [Presentation] Observing biomolecules through a lens of computer simulation (2021)
  • Author(s): 北尾彰朗, TRAN Phuoc Duy
  • Organizer: C2C Program Kick off symposium
  • Int'l Joint Research / Invited
• [Presentation] PaCS-MD/MSM to investigate protein motions and association/dissociation of protein complexes (2021)
  • Author(s): Akio Kitao
  • Organizer: Symposium on Computer Simulations and Cryo-ET/EM of Complex Biomolecular Systems
  • Int'l Joint Research / Invited
• [Presentation] Molecular movie of protein association/dissociation dynamics (2021)
  • Author(s): 北尾彰朗
  • Organizer: 第59回日本生物物理学会年会シンポジウム（原子レベルの動的構造解析が拓く生体分子機能の理解）
  • Invited
• [Presentation] Roles of hydration/dehydration for dissociation, association and stabilization of protein complexes (2021)
  • Author(s): Akio Kitao
  • Organizer: Pacific Chem 2021
  • Int'l Joint Research / Invited
• [Presentation] Transport mechanisms of ions, peptides and proteins through the biological membrane (2021)
  • Author(s): Akio Kitao
  • Organizer: Pacific Chem 2021
  • Int'l Joint Research / Invited
• [Presentation] Atomic mechanism of the complete association of intrinsically disordered peptide to protein (2021)
  • Author(s): Duy Tran, Akio Kitao
  • Organizer: XXXII IUPAP Conference on Computational Physics(ccp2021)
  • Int'l Joint Research
• [Presentation] 結合速度論解析 (2021)
  • Author(s): 北尾彰朗
  • Organizer: 「富岳」2021ワークショップ
  • Invited
• [Presentation] Application of ColDock to docking of cryptic pockets (2021)
  • Author(s): Ryunosuke Kiuchi, Kazuhiro Takemura, Akio Kitao
  • Organizer: 第59回日本生物物理学会年会
• [Presentation] DNA bending enhances the dissociation of tetrameric p53’s coredomains (2021)
  • Author(s): Duy Tran, Akio Kitao
  • Organizer: 第59回日本生物物理学会年会
• [Presentation] Unguided Binding MD of Protein-Protein Complexes by PPI-ColDock (2021)
  • Author(s): Kazuhiro Takemura, Akio Kitao
  • Organizer: 第59回日本生物物理学会年会
• [Presentation] Dynamics of Close-Open State of CALB Obtained by Parallel Cascade Molecular Dynamics Simulation and The Markov State Model (2021)
  • Author(s): Wijaya Tegar N., 北尾彰朗
  • Organizer: 第21回日本蛋白質科学会年会
• [Presentation] Investigating the dissociation process and kinetic rates of DBD-p53/DNA complex by PaCS-MD and MSM (2021)
  • Author(s): マルゾーク モハメド, 北尾彰朗
  • Organizer: 第21回日本蛋白質科学会年会
• [Presentation] Unguided Binding MD of Protein-Protein Complexes by PPI-ColDock (2021)
  • Author(s): 竹村和浩, 北尾彰朗
  • Organizer: 第21回日本蛋白質科学会年会
• [Presentation] Benchmarking the free energy calculation of PaCS-MD/MSM (2021)
  • Author(s): チャン フ ズイ, 畑 宏明,中矢 光, 北尾彰朗
  • Organizer: 第21回日本蛋白質科学会年会
• [Presentation] Predicting the complex conformations of protein/intrinsically disordered peptide complexes using a method termed a/dPaCS-MD (2021)
  • Author(s): Duy Phuoc Tran, Akio Kitao
  • Organizer: The Protein Society-35th Anniversary Symposium
  • Int'l Joint Research
• [Presentation] Binding free energy calculation with dPaCS-MD/MSM (2021)
  • Author(s): Duy Phuoc Tran, Akio Kitao
  • Organizer: C2C Program Kick off symposium
  • Int'l Joint Research
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