蛋白質情報科学研究室

メンバー

教授 中村 春木
肥後 順一(客員)
准教授 金城 玲
福田 育夫(客員)
助教 土屋 裕子
技術職員 小佐田 高史(技術専門職員)

 

連絡先

電話番号 06-6879-4311
ファックス番号 06-6879-8636
メールアドレス
URL http://www.protein.osaka-u.ac.jp/rcsfp/pi/index_pi.html

研究概要

本研究室は、蛋白質研究所で進めている蛋白質立体構造データベース(PDBj: Protein Data Bank Japan: http://www.pdbj.org/)を活用し、蛋白質および関連する生体分子の構造・物性・相互作用を、構造バイオインフォーマティクス研究とシミュレーション計算によって解析し、蛋白質構造情報の総合的な理解を目指している。さらに、PC クラスターや GPU で稼働する並列化プログラム開発を行い、量子化学と古典力学の連成計算(hybrid-QM/MM)を含む分子シミュレーションを実施し、蛋白質機能を電子状態から解析する研究も進めている。

prof.nakamuraFig19_2
Fig. 1: Composite Structural Motifs of Binding Sites for Delineating Biological Functions of Proteins Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs that represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures. (Kinjo AR, Nakamura H (2012) PLoS ONE 7(2): e31437)
prf.nakamura19_1
Fig.2: Molecular structures and redox active molecular orbitals (RAMOs) of the Cu2S2 core and ligand coordinating models of the CuA site in cytochrome c oxidase The CuA site functions as an electron transfer intermediate in cytochrome c oxidase (CcO) and nitrous oxide reductase N2OR). The X-ray structures of CcO revealed that the CuA site contains two copper ions bridged by two cysteinyl thiolate groups, and that each copper ion is coordinated equatorially with a histidine residue and axially with either a methionine residue or a carbonyl group of the polypeptide backbone. The Cu-Cu distance is remarkably short enough to allow the formation of a direct bond between the two copper ions. The reduced CuA site has a Cu(1+)-Cu(1+) core, which is oxidized by one electron. In the oxidized state, the CuA site is a completely delocalized mixed-valence Cu(1.5+)-Cu(1.5+) species. Many synthetic modeling studies also elucidated the important structural features for electronic and functional properties of the CuA site. The complex shows a mixed-valence oxidized state, as well as the CuA site, but has a longer Cu-Cu distance of 2.9 Å, which implies no direct Cu-Cu bond interaction. The mixed-valence synthetic model has a singly occupied πu redox active molecular orbital (RAMO), while that the oxidized CuA site shows a completely delocalized σu* ground state, in which an unpaired electron occupies the σu* RAMO. The completely delocalized σu* RAMO produces the stronger electronic coupling between two copper ions, which provides a strongly stabilized and delocalized electronic structure. This electronic structure greatly contributes to maintain the CuA site delocalized in the low-symmetry protein environment. In order to elucidate what factors are responsible for the stabilization of the σu* ground state of the CuA site, the electronic structures of the Cu2S2 core of the CuA site in CcO have been studied, using the density functional theory (M06) to elucidate the origin of the σu* ground state of the CuA site. Our computational results also demonstrated that the πu state, where the πu RAMO has an unpaired electron, is more stable than the σu* state even in the short Cu-Cu distance of 2.35 Å in the oxidized state. A decrease in the Cu-Cu distance generates stronger Cu-Cu and weaker S-S orbital interactions, leading to a small energy gap between the σu* and πu states, but the πu state is still more stable than the σu* state. The ligand coordinating model (full model) of the CuA site exhibits the σu* ground state. These findings imply that not only the direct Cu-Cu interaction but also the ligand coordination are responsible for the stabilization of the σu* state rather than the πu state in the CuA site. (Takano Y, Shigeta Y, Koizumi K, Nakamura H (2012) Int. J. Quantum. Chem. 112, 208-218)

 

研究課題

  1. 蛋白質の構造と相互作用を解析・予測するバイオインフォーマティクス研究
  2. 蛋白質および蛋白質・基質複合体の構造とエネルギーを数値シミュレーションによって得るための統計力学的アルゴリズムの開発と、量子化学と古典力学の連成計算を含む分子シミュレーションの実施

発表論文

  1. Composite structural motifs of binding sites for delineating biological functions of proteins. Kinjo, A. R., Nakamura, H. (2012) PLoS One 7:e31437.
  2. Electronic structures of the [4Fe-4S] cluster in dark-operative protochlorophyllide oxidoreductase (DPOR). Takano, Y., Yonezawa, Y., Fujita, Y., Kurisu, G., Nakamura, H. (2012) Chem. Phys. Lett. 503: 296.
  3. A Free-Energy Landscape for Coupled Folding and Binding of an Intrinsically Disordered Protein in Explicit Solvent from Detailed All-Atom Computations. Higo J., Nishimura, Y., Nakamura, H. (2011) J. Ame. Chem. Soc. 133: 10448.
  4. Molecular dynamics scheme for precise estimation of electrostatic interaction via zero-dipole summation principle. Fukuda, I., Yonezawa, Y., Nakamura, H. (2011) J. Chem. Phys. 134: 164107.
  5. Intra- and Intermolecular Interaction Inducing Pyramidalization on both sides of a Proline Di-peptide during Isomerization: an ab Initio QM/MM Molecular Dynamics Simulation Study in explicit water. Yonezawa, Y., Nakata, K., Sakakura, K., Takada, T., Nakamura, H. (2009) J. Am. Chem. Soc. 131: 4535.