Duan Hui, Zhao De-Rui, Liu Meng-Ting, Yang Li-Quan, Sang Peng
College of Agriculture and Biological Science, Dali University, Dali 671000, China.
Key Laboratory of Bioinformatics and Computational Biology of the Department of Education of Yunnan Province, Dali University, Dali 671000, China.
Int J Mol Sci. 2025 Jun 27;26(13):6226. doi: 10.3390/ijms26136226.
Activating mutations in the epidermal growth factor receptor (EGFR) are key oncogenic drivers across multiple cancers, yet the structural mechanisms by which these mutations promote persistent receptor activation remain elusive. Here, we investigate how three clinically relevant mutations-T790M, L858R, and the T790M_L858R double mutant-reshape EGFR's conformational ensemble and regulatory network architecture. Using multiscale molecular simulations and kinetic modeling, we show that these mutations, particularly in combination, enhance flexibility in the αC-helix and A-loop, favoring activation-competent states. Markov state modeling reveals a shift in equilibrium toward active macrostates and accelerated transitions between metastable conformations. To resolve the underlying coordination mechanism, we apply neural relational inference to reconstruct time-dependent interaction networks, uncovering the mutation-induced rewiring of allosteric pathways linking distant regulatory regions. This coupling of conformational redistribution with network remodeling provides a mechanistic rationale for sustained EGFR activation and suggests new opportunities for targeting dynamically organized allosteric circuits in therapeutic design.
表皮生长因子受体（EGFR）中的激活突变是多种癌症的关键致癌驱动因素，然而这些突变促进受体持续激活的结构机制仍不清楚。在这里，我们研究了三种临床相关突变——T790M、L858R和T790M_L858R双突变体——如何重塑EGFR的构象集和调节网络结构。使用多尺度分子模拟和动力学建模，我们表明这些突变，特别是组合突变，增强了αC螺旋和A环的灵活性，有利于激活态。马尔可夫状态建模揭示了平衡向活性宏观状态的转变以及亚稳态构象之间的加速转变。为了解决潜在的协调机制，我们应用神经关系推理来重建时间依赖性相互作用网络，揭示了突变诱导的连接远距离调节区域的变构途径的重新布线。这种构象重新分布与网络重塑的耦合为EGFR的持续激活提供了一个机制原理，并为在治疗设计中靶向动态组织的变构回路提供了新的机会。
