酵素の組み合わせ組成と設計

R Lipsh-Sokolik¹, O Khersonsky¹, S P Schröder²

¹Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel.

Science (New York, N.Y.)

|January 12, 2023

まとめ

研究者らは新しい計算方法である酵素の組み立てと設計 (CADENZ) を開発し,新しい酵素を作成した. この戦略により,何千もの多様で機能的な酵素が生成され,タンパク質の設計原理が進歩しました.

科学分野:

タンパク質工学と計算生物学
酵素の設計と構造-機能関係
生化学における機械学習の応用

背景:

酵素の構造と機能は,適切な折り畳みに必要な複雑な長距離相互作用によって制限されます.
特定の機能を持つ新しい酵素を設計することは,これらの折り畳みの制約のために困難です.

研究の目的:

構造的に多様な酵素を設計するための新しい計算戦略である酵素の組み合わせ組立と設計 (CADENZ) を導入する.
機能的な触媒部位を持つ安定した低エネルギー酵素構造を生成する.

主な方法:

結合酵素断片の組み立てに原子学と機械学習のアプローチを使用した.
エンドキシラナーゼの設計にCADENZ戦略を適用した.
機能的な酵素の設計を特定し回復するために,活動に基づくタンパク質プロファイリングを使用します.

主要な成果:

CADENZの戦略を用いて数千の構造的に異なったエンドキシラナーゼを成功裏に復元した.
機能性酵素の設計は,事前に組織された活性部位と,コンパクトで安定した非活性部位パッキングを特徴としています.
設計成功率を10倍に改善し,CADENZの繰り返し精製後に10,000以上の酵素を回復しました.

結論:

CADENZ戦略は,多様な,安定した,機能的な酵素構造を生成するための酵素断片の組み合わせ設計を可能にします.
アクティブ・サイト・プレオーガナイゼーションやパッケージングの改善など,機能的なデザインから得た教訓は,CADENZの方法を強化します.
この繰り返し設計・テスト・学習アプローチは,新しいタンパク質の機能と設計原理の発見のために,モジュラータンパク質ファミリーに広く適用できます.

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