P14

加⽔分解酵素の機能制御に向けた共溶媒添加効果の全原⼦MD解析○⼤坂⿓司 1, ⽯⽥豊和 2, 笠原健⼈ 1, 松林伸幸 12産業技術総合研究所② System① Introduction

溶質(Xylanase)

バイオ燃料⽣産
⾷品加⼯での⽤途

⽣体触媒（酵素）
選択性、環境負荷 → ⼯業的利⽤価値
Xylanase

Xylan(多糖)1阪⼤院基礎⼯

共溶媒(1.0 M)

反応前(R)

遷移状態(TS)

ジメチルスルホキシド(DMSO)
尿素(urea)

D-Xylose(単糖)エチレングリコール(EG)
1,6-ヘキサンジオール(HexDiol)
グリセリン(glycerine)
P. Bajaj, et al., Appl. Microbiol., 103, 8711–8724 (2019).

酵素活性の制御のために共溶媒効果→ 安価、濃度による連続的な制御

変異タンパク質→ ⾼価、制御が離散的T. Ishida, et al., J. Am. Chem. Soc., 142, 17966-17980 (2020).

R,TS
純⽔溶液系

200 ns
10 ns 10 ns
・・・

研究⽬的
Xylanaseの酵素活性の連続制御に向けた活性化⾃由エネルギーに対する共溶媒効果の解明① 溶質構造をサンプリング

溶質固定
20 ns

② 純⽔系および混合溶媒系でMD(同じ溶質構造)③ 活性化⾃由エネルギー計算③ Theory
過剰化学ポテンシャル

Xylanase

⾃由エネルギー

活性化⾃由エネルギーと共溶媒効果
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過剰化学ポテンシャルTSµex = 溶質内エネルギー + 溶媒和⾃由エネルギー ⌫ + 溶質の構造エントロピー<latexit sha1_base64="lbxP3RjmCLktulLCpuzDU4HSQG8=">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</latexit><latexit sha1_base64="NtR8c3wnXB6asoWqVHR3q7Z8BYk=">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</latexit>µexTS<latexit sha1_base64="tgGY9HkqhSgXfYVX19mHX80a80E=">AAAClXichVHLShxBFD220Yxj1IlZRMhGHBRXwx3RRARBjEh2PsZRwdahu6fUZvpFd82gafoH/ABdZBVBgvgL7kTxB1z4CeJSwY2L3OlpFBX1Nl117ql7bp2q0j3LDCTRZZPS/KGl9WOqLd3+qaOzK/O5ezFwq74hioZruf6yrgXCMh1RlKa0xLLnC83WLbGkV37W15dqwg9M11mQ255YtbUNx1w3DU0yVcqQGvcIfVGO1LKwpKba1VKo2prc9O1woRBFaw+Z2IqiUiZLOYqj9yXIJyCLJGbdzD+oKMOFgSpsCDiQjC1oCPhbQR4Ej7lVhMz5jMx4XSBCmrVVrhJcoTFb4XGDs5WEdTiv9wxitcG7WPz7rOxFP13QId3QOR3RFd2/2iuMe9S9bPOsN7TCK3Xt9BTu3lXZPEtsPqre9CyxjtHYq8nevZipn8Jo6Gu/924KY/P94QDt0zX7/0uXdMIncGq3xsGcmP+DND9A/vl1vwSLQ7n899zI3HB2YjJ5ihS+oQ+DfN8/MIFfmEWR993FMU5xpnxVxpUpZbpRqjQlmi94EsrMf6Tans8=</latexit>

溶媒環境に関する変分原理<latexit sha1_base64="1H3+xWb0ITjfSnoI63CMjZk3Fus=">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</latexit><latexit sha1_base64="oFQMOUj9IyMuM+sp6hy4S5XsTNM=">AAAClHichVHLLgRBFD3aa4zXIBGJjZgQq1EjXhELIRIrYRgkmkl3T6Ez/Up3zQSd/gF7sbAiERGfYInED1j4BLEksbFwp6dDENxOV5176p5bp6pUx9A9wdhDlVRdU1tXH2uINzY1t7Qm2tpXPLvoajyr2YbtrqmKxw3d4lmhC4OvOS5XTNXgq2phpry+WuKup9vWsthz+IapbFv6lq4pgqhcYlAOe/guzwdynhtCkc1izpdNRey4pp8Jgs2PhO8GQS6RZCkWRs9PkI5AElEs2IlzyMjDhoYiTHBYEIQNKPDoW0caDA5xG/CJcwnp4TpHgDhpi1TFqUIhtkDjNmXrEWtRXu7phWqNdjHod0nZgz52zy7YM7tjl+yRvf3ayw97lL3s0axWtNzJtR50Lb3+qzJpFtj5VP3pWWAL46FXnbw7IVM+hVbRl/aPnpcmMn1+PztlT+T/hD2wazqBVXrRzhZ55hhxeoD09+v+CVaGUunR1MjicHJqOnqKGLrRiwG67zFMYQ4LyNK+h7jCDW6lTmlSmpFmK6VSVaTpwJeQ5t8BwsCecA==</latexit>

共溶媒

µex
R

R

K. Masutani, et al., J. Chem. Phys., 150, 14 (2019).

µex,wat
TS

純⽔中
混合溶媒

<latexit sha1_base64="EO8aj8q7YEfFP/sTv+6B0nwkcF0=">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</latexit>µex,mix
混合溶媒中

反応座標

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活性化⾃由エネルギーの共溶媒効果µex,mix
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Gmix
act
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ex,mixGwat
act = (µTS

Gmix
act
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RGact < 0 ︓共溶媒が反応を促進<latexit sha1_base64="vhsgVUiX+0jPGfzDLVi+7UO4F6w=">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</latexit>

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Gact の計算には溶媒和⾃由エネルギーh ⌫iを計算すればいい<latexit sha1_base64="RfkzylKs4hJ6blY9IuyfgzXmPtQ=">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</latexit><latexit sha1_base64="zyxw4yoju65SYCU+f6KwGuBZR/s=">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</latexit>④ Result & Discussion
活性化⾃由エネルギー

DMSOの寄与分割と活性化⾃由エネルギーとの相関<latexit sha1_base64="zyxw4yoju65SYCU+f6KwGuBZR/s=">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</latexit>

DMSOの相互作⽤解析 残基別分割

Gact =静電＋vdW＋排除体積＋その他（多体間）
𝑅! = 0.362

𝑅! = 0.904

averagesample1

sample2

diff.

𝑅! = 0.000189

𝑅! = 0.702

sample3<latexit sha1_base64="O7DQvvo8oSOatqT5zXX2X3GrCYw=">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</latexit>

cosolvent

Gact

error

(-)

(kcal/mol)(kcal/mol)

DMSO

-2.61

2.02

urea

3.63

2.34

EG

1.68

1.39

HexDiol

5.12

1.95

glycerine

-0.70

2.21

elecと強い相関
elecの絶対値を⼤きくすることが反応の制御に重要活性部位の周辺⑤ Conclusion
・ジメチルスルホキシドは反応促進、尿素,エチレングリコール,1,6–ヘキサンジオールは反応抑制、グリセリンは反応にほとんど影響しない
・静電相互作⽤の絶対値増⼤が活性の制御に最も効果的である・反応を促進させる共溶媒であるDMSOの場合、特に活性部位周りの残基と強く相互作⽤するタンパク質構造がある