スパコンで迫る生体分子の働き
宮下治

細胞 ミトコンドリア
細胞核OpenStax College - Anatomy & Physiology, Connexions Web site.
http://cnx.org/content/col11496/1.6/

細胞から分子へ

Credit: Cell: Mariana Ruiz Villarreal, ribosome & ATP synthase David Goodsell - RCSB PDB Molecule of the Month, DNA Zephyris

目的：生物分子を理解し医学へつなげる

インフルエンザ
ウイルスが細胞に取り込まれる
過程

R. Palmer, Nature 2011

inactivator concentrations, such that individual
kinetic parameters (Ki and ki) could not be determined; only a second-order rate constant ki/Ki of
196 min−1 mM−1 could be measured. Turnover ofthe covalent intermediate (khydr) also occurred
rapidly, with a t1/2 < 1 min. Confirmation of theformation of a covalent species and identification

Fig. 1. Structures of key influenza therapeutics, mechanism of action of
DFSAs, and x-ray structure of inhibited enzyme. (A) Chemical structures ofcell surface sialic acids, the neuraminidase transition state, zanamivir (Relenza),and oseltamivir (Tamiflu). (B) Mechanism of action of the DFSAs. (C) X-ray crystallographic structure of the active site of the enzyme trapped as its 3-fluoro(eq)-4guanidino-sialyl-enzyme intermediate (elimination product is in pale cyan) overlaid72

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optimized, as well as the relative rate constants
for formation (ki) and hydrolysis (khydr) of thetrapped intermediate, with the objective being tooptimize the ratio of ki/khydr. Versions of 1 bearing
amine (Am) and guanidine (Gu) substituents at
C-4 were of interest because these cationic substituents might improve the initial affinity andwith omit (22) electron density map shown as a gray mesh contoured at 1s within
1.6 Å of ligands. The electron density extends from the ligand molecule toY406, suggesting a covalent link between the inhibitor’s C-2 atom and the OHof Y406. (D) Diagram of interactions (orange dashed lines; distances in Å) withthe sialic acid in the covalently inhibited enzyme. The corresponding diagramof interactions for the elimination product is shown in fig. S4.

SCIENCEwww.sciencemag.org

Downloaded from www.sciencemag.org on July 28, 2013

ance to structurally conservative, mechanismbased inhibitors should be a much less probable
event (2–10).
NAs catalyze the hydrolysis of sialosides withnet retention of stereochemistry at the site of substitution. A mechanism involving an ion-pair intermediate has long been suggested for the GH34

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生物分子を見る実験方法
NMR

Cyanovirin-N, Sandstom, etal

データ解析

電子顕微鏡

X線結晶解析，自由電子レーザー

RNA sponge, Song, Gallagher-Jones, et al

David J Morgan fromCambridge, UK - Tecnai
12 Electron Microscope多数のデータを使った立体像の構築

Particle stream

Stopper

X-ray beam
Diffraction pattern
recorded on apixelated detector

実験データ

K. J. Gaffney and H. N. Chapman, Science (2007) 316 1444-1448

角度の推定

立体構造モデル

phaseretrieval

Structure Factor (3Dstructure in Fourierspace)

スーパーコンピューターにより百万画像の解析を可能にする• 実験データをもとに決定した生体分子の構造は静止画像• 実際は常に動いているが，観測は難しい• 分子動力学シミュレーションにより，運動の様子を知ることができる．

分子をプログラムで表現
水分子 H2O

量子力学

古典力学

2013ノーベル化学賞

分子をプログラムで表現

パラメーター分子の動きをコンピューターで再現

１．力の計算２．ニュートンの運動方程式を解く（少しずつ近似的に）１回のサイクル=フェムト秒=10-15秒

膨大な計算量• 生物は複雑• 現在のシミュレーションは，単純なごく一部のほんの一瞬

n [4], this1s A
one of x109
1msly usedocesses

1µs

milestoneat thewith time,

1ps

107106105B

C

106105103
1980 1990 2000 2010 2020

108107104

1nsan

細胞分・時間1041031980 1990 2000 2010 2020
Vendruscolo & Dobson, Current Biology 2010

Figure 1. Moore’s law in molecular biology.

2000
1990

220ps ps us m

長いシミュレーションをする工夫• 粗視化モデル• 拡張シミュレーション• スーパーコンピューター• 並列化プログラム

Atomistic bacterial cytoplasm simulation
Research article

Biophysics and Structural Biology Computational and Systems Biology

Figure 1. Molecular model of a bacterial cytoplasm. (A) Schematic illustration of Mycoplasma genitalium (MG). (B) Equilibrated MGh system highlighted
with proteins, tRNA, GroEL, and ribosomes. (C) MGh cl ose-up showing atomistic level of detail. See also supplementary Figures 1 and 2 for structuresof individual macromolecules and metabolites as well as supplementary Figure 3 for initial configurations of the simulated systems.
DOI: 10.7554/eLife.19274.003

Yu et. al. eLife 2016;5:e19274

スパコンで迫る生体分子の働き• 生体分子の働く仕組みを知り，医療につなげる．

• 実験による観測とコンピューターによるデータ解析• 動きを理解するための運動シミュレーション

謝辞• 理研AICS
松永康佑，杉田有治，Florence Tama，土井陽子• 公益財団法人計算科学振興財団
研究拠点（COE)形成推進事業