基于结构动力学的EGFR罕见突变型(S768I)致NSCLC分子机制研究  

Molecular mechanism of EGFR rare mutation(S768I)-induced NSCLC based on structural dynamics

作　　者：王雨婷 刘梦婷 王妍雯 侯清梅 杨力权 桑鹏 WANG Yu-Ting;LIU Meng-Ting;WANG Yan-Wen;HOU Qing-Mei;YANG Li-Quan;SANG Peng(College of Agriculture and Biological Science,Dali University,Dali 671003,China;Key Laboratory of Bioinformatics and Computational Biology of the Department of Education of Yunnan Province,Dali University,Dali 671003,China)

机构地区：[1]大理大学农学与生物科学学院,大理671003 [2]大理大学云南省教育厅生物信息与计算生物学重点实验室,大理671003

出　　处：《原子与分子物理学报》2025年第1期41-48,共8页Journal of Atomic and Molecular Physics

基　　金：国家自然科学基金(31860243)。

摘　　要：表皮生长因子受体(EGFR)基因突变是导致非小细胞肺癌(NSCLC)的重要诱因.S768I点突变作为EGFR的一种罕见突变,目前尚无标准的靶向治疗方法,因此详细了解EGFR S768I突变体与野生型的结构差异对于开发相关药物至关重要.为了探究S768I突变在NSCLC中的作用,对WT-EGFR和S768I-EGFR进行分子动力学(MD)模拟、本质动力学(ED)分析和自由能图谱(FEL)重构.MD模拟表明S768I突变增加了EGFR的全局和局部柔性;ED分析得出的大尺度协同运动表明,区分活性状态和非活性状态的两个重要结构元件A-loop和αC-helix在S768I-EGFR中比在WT-EGFR中具有更明显的过渡到活动状态的趋势;自由能计算显示S768I-EGFR的FEL比WT-EGFR的更粗糙更复杂,这意味着S768I突变体具有更丰富的构象多样性.研究结果为S768I突变导致NSCLC提供了合理的分子机理解释,并为开发针对S768I突变患者的新靶向治疗药物提供帮助.Epidermal growth factor receptor(EGFR)gene mutation is an important cause of non-small cell lung cancer(NSCLC).The S768I point mutation is a rare mutation of EGFR,and there is no standard targeted therapy at present.Therefore,a detailed understanding of the structural differences between the EGFR S768I mutant and the wild type(WT)is crucial for the development of related drugs.In order to probe the role of the S768I mutation in NSCLC,we performed molecular dynamics(MD)simulations,essential dynamics(ED)analyses,and free energy landscape(FEL)constructions on WT and S768I mutant EGFR.MD simulations suggest that the S768I mutation increases both of the global and local flexibility of EGFR.The large concerted motions derived from ED analyses indicate that two important structural elements A-loop andαC-helix which distinguish the active state from the inactive state both have a more pronounced tendency to transition to the active state in S768I mutant than in WT.The free energy calculations reveal a more rugged and complex FEL for the S768I mutant than for the WT EGFR,implying that the mutant form has a richer conformational diversity.The study provides a reasonable molecular mechanism explanation for S768I mutations leading to NSCLC,and provide assistance for the development of new targeted therapeutic drugs for patients with S768I mutations.

关 键 词：表皮生长因子受体(EGFR) S768I 分子动力学模拟 本质动力学 自由能图谱 

分 类 号：O561[理学—原子与分子物理]