ラッソペプチド: 折り畳み可能な自然界の最も小さな相互接続したモチーフの探索

Gabriel C A da Hora¹, Myongin Oh¹, Marcus C Mifflin¹

¹Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.

Journal of the American Chemical Society

|January 3, 2024

まとめ

コンピュータによるシミュレーションにより,新しいペプチドの折りたたみは稀であることが明らかになった. しかし,配列と反応条件を改変することで,ラッソ前構造を安定させ,治療開発を助けることができます.

科学分野:

自然製品化学
コンピュータ生物学
バイオ物理学

背景:

ラッソペプチドは独特の糸状構造を持つ自然産物です
小さいサイズと安定性により治療的な可能性はありますが合成は折りたたみの複雑さによって制限されています
新しい折り畳みを理解することはこれらの分子へのアクセスに不可欠です

研究の目的:

シミュレーションを用いて,抗微生物ラッソペプチドマイクロシンJ25 (MccJ25) の折り畳み傾向を調査する.
糸状/非糸状の前駆物質を区別し,ハンドル性を決定するためのアルゴリズムを開発する.
新しいペプチドの折り畳みを容易にするための戦略を特定する.

主な方法:

MccJ25の折り畳みを研究するために,分子動力学シミュレーションが使用されました.
ペプチド構造と折り畳み経路を分析するために新しいアルゴリズムが開発されました.
配列の修正,非自然な機能,pH条件が調査されました.

主要な成果:

MccJ25は右利きプレ・ラッソスを形成し,以前の予測に反する.
ネイティブ・プレ・ラッソ・ストラクチャはメタステーブルで展開状態を好みます
修正された配列と条件 (例えばヒスティジンプロトネーション) は,プレ・ラッソ形状を著しく安定させる.

結論:

ラッソペプチドのデノボの折り畳みは,固有の不安定性のために一般的にまれである.
計算方法は,ラッソペプチドの折り畳みを特徴付けるのに価値があります.
配列を最適化し,非自然的な改変を行い,反応条件を制御することで,治療用途のためのラッソ構造の形成が容易になります.

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