2023-06-19 アルゴンヌ国立研究所(ANL)
◆この研究では、UICのAo Ma准教授と彼の学生たちはTheta上で分子動力学シミュレーションを行い、それを数学的な手法を用いて分析しました。タンパク質は常に動き続けていますが、Maはタンパク質内のどの要素が最終的にその構造変化を制御しているのかを知りたかったのです。研究によれば、HIVプロテアーゼの構造変化を完全に決定するのに必要な6つの反応座標を特定することができました。
◆これにより、フラップオープニングの発生方法を特定することができ、このウイルスの分子メカニズムを正確に理解するための大きな進歩となり、薬の発見における新たな戦略や標的を生み出すことが期待されます。
<関連情報>
- https://www.anl.gov/article/scientists-use-argonne-supercomputer-to-detail-hiv-protein-mechanism-crucial-for-drug-development
- https://www.pnas.org/doi/10.1073/pnas.2214906119
HIV-1プロテアーゼのフラップ開口部の正確な反応座標を発見 Exact reaction coordinates for flap opening in HIV-1 protease
Shanshan Wu, Huiyu Li, and Ao Ma
Proceedings of the National Academy of Sciences Published:December 2, 2022
DOI:https://doi.org/10.1073/pnas.2214906119
Significance
The primary goal of protein studies is to understand how proteins function, which requires understanding the functional dynamics responsible for transitions between different protein conformations. The key to success is to identify the reaction coordinates, the small number of essential coordinates that control functional dynamics. Starting with the pioneering paper of Du et al. and seminal works of Chandler group in late 1990s, intensive efforts have been devoted to identifying reaction coordinates in complex molecules. This remains a major challenge. Using the recently developed generalized work functional, we successfully identified the reaction coordinates for flap opening of the HIV-protease, an essential process of this complex protein and major drug target. This success marks an important step toward understanding protein functional dynamics.
Abstract
The primary goal of protein science is to understand how proteins function, which requires understanding the functional dynamics responsible for transitions between different functional structures of a protein. A central concept is the exact reaction coordinates that can determine the value of committor for any protein configuration, which provide the optimal description of functional dynamics. Despite intensive efforts, identifying the exact reaction coordinates (RCs) in complex molecules remains a formidable challenge. Using the recently developed generalized work functional, we report the discovery of the exact RCs for an important functional process—the flap opening of HIV-1 protease. Our results show that this process has six RCs, each one is a linear combination of ~240 backbone dihedrals, providing the precise definition of collectivity and cooperativity in the functional dynamics of a protein. Applying bias potentials along each RC can accelerate flap opening by 103 to 104 folds. The success in identifying the RCs of a protein with 198 residues represents a significant progress beyond that of the alanine dipeptide, currently the only other complex molecule for which the exact RCs for its conformational changes are known. Our results suggest that the generalized work functional (GWF) might be the fundamental operator of mechanics that controls protein dynamics.
