| Cite this article as: Wang Yu-Ting,Liu Meng-Ting,Wang Yan-Wen,Hou Qing-Mei,Yang Li-Quan,Sang Peng. Molecular mechanism of EGFR rare mutation (S768I)-induced NSCLC based on structural dynamics [J]. J. At. Mol. Phys.(原子与分子物理学报), 2025, 42: 011007 (in Chinese) |
| Molecular mechanism of EGFR rare mutation (S768I)-induced NSCLC based on structural dynamics |
| Hits 71 Download times 23 Received:April 27, 2023 Revised:June 14, 2023 |
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| DOI
10.19855/j.1000-0364.2025.011007 |
| Key Words
EGFR S768I molecular dynamics simulation essential dynamics free energy landscape |
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| Abstract
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| 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 and αC-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. |
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