転写因子DNA探索のエネルギーランドスケープ理論：速度‐親和性パラドックス

• Project Area: Integral understanding of the mechanism of transcription cycle through quantitative, high-resolution approaches
• Project/Area Number: 25118509
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: 高田 彰二 京都大学, 理学(系)研究科(研究院), 教授 (60304086)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2013: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: 転写因子 / エネルギーランドスケープ / シミュレーション

Outline of Annual Research Achievements

本研究の目的は、構造に基づく分子シミュレーションと数理モデリングとによって、転写因子のDNA探索機構の新しい描像を構築することである。研究は３つのアプローチより構成される。
A)原子レベルの分子動力学シミュレーション（原子レベルMD）：特異的、半特異的なDNA配列上において、転写因子がDNAとどのように結合するか、構造と結合エネルギーを解析した。任意性の少ない原子レベルMDを実施し、結果を以下のシミュレーションにつなげた。
B)粗視化レベルの分子動力学シミュレーション（CGMD）：Aの原子レベルMDに基づき粗視化モデルを構築し、広範なDNA配列上の転写因子の拡散過程をCGMDした。特異的DNA配列から、非特異的配列まで、さまざまな配列について、そのDNAとの親和性と、拡散速度を解析した。粗視化モデルとしては、我々が過去10年にわたり開発・改良してきた高精度粗視化モデルを用いた。転写因子（蛋白質）ではアミノ酸1個を１粒子で、DNAについてはヌクレオチド1個を3粒子で、各々表現した。
C)数理モデリング：BのCGMD計算で得られる配列の特異性と速度－親和性との相関関係を与えて、数理モデルの中で拡散によるDNA探索の速度論を展開した。
具体的には、A)非特異的DNA配列を用意し、原子レベルMDによって、結合モード（構造）と結合エネルギー評価を行った。B)原子レベMDに基づき粗視化モデルを構築し、広範なDNA配列上の転写因子の拡散過程をCGMDを実施した。C)可能な範囲で、CGMD計算で得られる配列の特異性と速度－親和性との相関関係を与えて、数理モデルの中で拡散によるDNA探索の速度論を導いた。細菌を対象として、ゲノム上での配列探索速度を計算し、実験と比較・検討した。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Modeling Structural Dynamics of Biomolecular Complexes by Coarse-Grained Molecular Simulations (2015)
  • Author(s): Shoji Takada, Ryo Kanada, Cheng Tan, Tsuyoshi Terakawa, Wenfei Li, and Hiroo Kenzaki
  • Journal Title: Accounts of Chemical Research Volume: 48 Issue: 12 Pages: 3026-3035
  • DOI: 10.1021/acs.accounts.5b00338
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] p53 dynamics upon response element recognition explored by molecular simulations (2015)
  • Author(s): Tsuyoshi Terakawa and Shoji Takada
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 17107-17107
  • DOI: 10.1038/srep17107
  • NAID: 120005758220
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Partial Unwrapping and Histone Tail Dynamics in Nucleosome Revealed by Coarse-Grained Molecular Simulations (2015)
  • Author(s): Hiroo Kenzaki and Shoji Takada
  • Journal Title: PLoS Computational Biology Volume: 11 Issue: 8 Pages: e1004443-e1004443
  • DOI: 10.1371/journal.pcbi.1004443
  • NAID: 120005947019
  • Peer Reviewed / Open Access
• [Journal Article] How Co-translational Folding of Multi-domain Protein Is Affected by Elongation Schedule: Molecular Simulations (2015)
  • Author(s): Tomohiro Tanaka, Naoto Hori, and Shoji Takada
  • Journal Title: PLoS Computational Biology Volume: 11 Issue: 7 Pages: e1004356-e1004356
  • DOI: 10.1371/journal.pcbi.1004356
  • NAID: 120005946993
  • Peer Reviewed / Open Access
• [Journal Article] On the Mg2+ binding site of the ε subunit from bacterial F-type ATP synthases (2015)
  • Author(s): Alexander Krah and Shoji Takada
  • Journal Title: Biochimica et Biophysica Acta - Bioenergetics Volume: 1847 Issue: 10 Pages: 1101-1112
  • DOI: 10.1016/j.bbabio.2015.05.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Couplings between Hierarchical Conformational Dynamics from Multi-Time Correlation Functions and Two-Dimensional Lifetime Spectra: Application to Adenylate Kinase (2015)
  • Author(s): J. Ono, S. Takada, and S. Saito
  • Journal Title: Journal of Chemical Physics Volume: 142 Issue: 21 Pages: 212404-212404
  • DOI: 10.1063/1.4914328
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] RESPAC : Method to Determine Partial Charges in Coarse-greined Prote in Model and Its Application to DNA-Binding Proteins' Journal of Chemical Theory and Computation (2014)
  • Author(s): Tsuyoshi Terakawa and Shoji Takadae
  • Journal Title: Journal of Chemical Theory and Computation Volume: 10 Issue: 2 Pages: 711-721
  • DOI: 10.1021/ct4007162
  • Peer Reviewed
• [Journal Article] Drug Uptake Pathways of Multidrug Transporter AcrB Studied by Molecular Simulations and Site-Directed Mutagenesis Experiments (2013)
  • Author(s): Xin-Qiu Yao, Nobuhiro Kimura, Satoshi Murakami, and Shoji Takada
  • Journal Title: Journal of the American Chemical Society Volume: 135 (20) Issue: 20 Pages: 7474-7485
  • DOI: 10.1021/ja310548h
  • Peer Reviewed
• [Journal Article] ATP hydrolysis mechanism in kinesin studied by combined quantum-mechanical molecular-mechanical metadynamics (2013)
  • Author(s): M. J. McGrath、I-F. W. Kuo, S.Hayashi, S. Takada
  • Journal Title: J. Amer. Chem. Soc. Volume: (in press) Issue: 24 Pages: 8908-891
  • DOI: 10.1021/ja401540g
  • Peer Reviewed
• [Journal Article] Bayesian parameter inference by Markov chain Monte Carlo with hybrid fitness measures: Theory and test in apoptosis signal transduction network (2013)
  • Author(s): Yohei Murakami and Shoji Takada
  • Journal Title: PLoS One Volume: 8(9) Issue: 9 Pages: 1-17
  • DOI: 10.1371/journal.pone.0074178
  • Peer Reviewed
• [Presentation] Structural insights into chromatin folding and transcriptional regulation (2015)
  • Author(s): Shoji Takada
  • Organizer: The International Chemical Congress of Pacific basin Societies 2015
  • Place of Presentation: Honolulu, Hawaii
  • Year and Date: 2015-12-15
  • Int'l Joint Research / Invited
• [Presentation] HU Binding Coupled Bending of Double Stranded DNA (2015)
  • Author(s): Cheng Tan，Tsuyoshi Terakawa, Shoji Takada
  • Organizer: 第53回日本生物物理学会年会
  • Place of Presentation: 金沢大学角間キャンパス（金沢市）
  • Year and Date: 2015-09-13
• [Presentation] Interaction of replication initiator protein DnaA with dsDNA studied by molecular dynamics simulation (2015)
  • Author(s): Masahiro Shimizu and Shoji Takada
  • Organizer: 回日本生物物理学会年会
  • Place of Presentation: 金沢大学角間キャンパス（金沢市）
  • Year and Date: 2015-09-13
• [Presentation] Computational modeling of chromatin & transcription factor by coarse-grained molecular simulations (2015)
  • Author(s): Shoji Takada
  • Organizer: Kyoto-Heidelberg Joint Workshop 2015, “Applied Mathematics, Scientific Computing, and Applications”
  • Place of Presentation: Kyoto,Japan
  • Year and Date: 2015-08-31
  • Int'l Joint Research / Invited
• [Presentation] 複製開始タンパク質DnaAと二重鎖DNA相互作用の分子動力学計算による解析 (2015)
  • Author(s): 清水将裕、高田彰二
  • Organizer: 転写サイクル合同班会議 2015
  • Place of Presentation: ホテル暖香園（伊東市）
  • Year and Date: 2015-08-03
• [Presentation] HU Binding, Sliding, and Bending of Double Stranded DNA: A Coarse-Grained Molecular Dynamics Simulation Study (2015)
  • Author(s): Cheng Tan and Shoji Takada
  • Organizer: 「柔らかな分子系」国際シンポジウム（第3回公開シンポジウム）
  • Place of Presentation: 日本科学未来館（東京都）
  • Year and Date: 2015-07-09
• [Presentation] 粗視化シミュレーションを用いたDNA複製開始複合体のモデリング研究 (2015)
  • Author(s): 清水将裕
  • Organizer: 第9回京阪奈計算生物物理セミナー
  • Place of Presentation: 関西光科学研究所（木津市）
  • Year and Date: 2015-03-17
• [Presentation] Functional Dynamics of Disordered Regions in Multi-Domain Proteins (2014)
  • Author(s): Shoji Takada
  • Organizer: Gordon Research Conference "Protein Folding Dynamics"
  • Place of Presentation: Texas, USA
  • Invited
• [Presentation] Specific DNA sequence search dynamics of p53 and effect of acetylation of its C-terminal domain: multi-scale simulation study (2014)
  • Author(s): Tsuyoshi Terakawa, Junichi Higo, Shoji Takada
  • Organizer: Biophysical Society 58th Annual Meeting
  • Place of Presentation: Moscone Center, San Francisco
• [Presentation] Large-Scale Functional Dynamics of p53 Studied by Multi-Scale Molecular Simulations (2013)
  • Author(s): Shoji Takada
  • Organizer: IMS Workshop on "Hierarchical Molecular Dynamics:From Ultrafast Spectroscopy to Single Molecule Measurements"
  • Place of Presentation: 岡崎コンファレンスセンター（岡崎市）
  • Invited
• [Presentation] Flexibility and specificity in protein-DNA complexes (2013)
  • Author(s): Shoji Takada
  • Organizer: International Symposium on Physical Principles and Underlying Mechanisms of Biomolecules and Materials
  • Place of Presentation: Beijing, China
  • Invited
• [Presentation] Specific DNA sequence search and recognition mechanism of tumor suppressor p53: Multi-scale simulation study (2013)
  • Author(s): Tsuyoshi Terakawa, Junichi Higo, Shoji Takada
  • Organizer: 転写サイクル合同班会議 2013
  • Place of Presentation: ホテルおかだ（神奈川県）
• [Presentation] Specific DNA sequence search and recognition mechanism of transcription factor p53: Multi-scale simulation study (2013)
  • Author(s): Tsuyoshi Terakawa, Junichi Higo, Shoji Takada
  • Organizer: 第7回分子科学討論会
  • Place of Presentation: 京都テルサ（京都市）
• [Presentation] Structure of model chromatin and dynamics of transcription factors studied by coarse-grained simulations (2013)
  • Author(s): Shoji Takada
  • Organizer: 第51回日本生物物理学会年会
  • Place of Presentation: 国立国際会議（京都市）
  • Invited
• [Presentation] Specific DNA sequence search and recognition mechanism of transcription factor p53: multi-scale simulation study (2013)
  • Author(s): Tsuyoshi Terakawa, Higo Junichi, Shoji Takada
  • Organizer: 第51回日本生物物理学会年会
  • Place of Presentation: 国立国際会議（京都市）
• [Presentation] DNA unwinding mechanisms in <i>E. coli, oriC</i> region studied by coarse grained molecular dynamics simulations (2013)
  • Author(s): Shimizu Masahiro, Shoji Takada
  • Organizer: 第51回日本生物物理学会年会
  • Place of Presentation: 国立国際会議（京都市）