School of Physics and Engineering, Henan University of Science and Technology, Luoyang 471023, P. R. China.
School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637551, Singapore.
Phys Chem Chem Phys. 2024 Oct 9;26(39):25480-25487. doi: 10.1039/d4cp02936d.
In this study, molecular dynamics simulations were used to systematically explore the reason why BH3-only protein BAD binds to anti-apoptotic protein BCL-L but not to MCL-1 to give more theoretical hints for the design of BAD mimetic inhibitors for the dual-targeting of BCL-L and MCL-1. Starting with the difference in residue-based binding energy contributions, a series of analyses were conducted to identify the hotspot residues in MCL-1 that significantly affect the interaction with BAD. Among them, the insertion of the T residue in the loop between α4 and α5 domains of MCL-1 is considered to be the main cause of BAD selective binding. The inserted T residue reduces the stability of the loop and weakens the hydrogen bond interactions that originally bound E19 of BAD in BCL-L/BAD, and the freed E19 severely interferes with the salt bridge between D16 and Arg53 by electrostatic repulsion. This salt-bridge is believed to be critical for maintaining the binding between BCL-L and BAD. By clarifying the reasons for differential binding, we can more specifically optimize the BAD sequence to target both BCL-L and MCL-1.
在这项研究中，使用分子动力学模拟系统地探索了 BH3 仅有蛋白 BAD 与抗凋亡蛋白 BCL-L 结合而不是与 MCL-1 结合的原因，为设计针对 BCL-L 和 MCL-1 的双重靶向的 BAD 模拟抑制剂提供了更多的理论提示。从基于残基的结合能贡献的差异开始，进行了一系列分析，以确定 MCL-1 中对与 BAD 相互作用有显著影响的热点残基。其中，MCL-1 中 α4 和 α5 结构域之间环上插入 T 残基被认为是 BAD 选择性结合的主要原因。插入的 T 残基降低了环的稳定性，并削弱了原本在 BCL-L/BAD 中结合 BAD 的 E19 的氢键相互作用，而游离的 E19 通过静电排斥严重干扰 D16 和 Arg53 之间的盐桥。据信，这种盐桥对于维持 BCL-L 和 BAD 之间的结合至关重要。通过阐明差异结合的原因，我们可以更具体地优化 BAD 序列，以针对 BCL-L 和 MCL-1。
