Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches

Author:

Wang Jun-Ling1,Liu Ming-Sheng2,Fu Yu-Dong3,Kan Qiang-Bo3,Li Chun-Yan4,Ma Rong1,Fang Zhe-Wei1,Liu Hong-Xia1,Li Meng-Xian1,Lv Jia-Ling4,Sang Peng5,Zhang Chao4ORCID,Li Hong-Wei1ORCID

Affiliation:

1. Clinical Laboratory, Kunming Medical University Affiliated Qujing Hospital , Qujing 655000 , China

2. Department of Urological Surgery, Kunming Medical University Affiliated Qujing Hospital, Qujing 655000 , China

3. Department of Thoracic Surgery, Kunming Medical University Affiliated Qujing Hospital, Qujing 655000 , China

4. Department of Oncology, Kunming Medical University Affiliated Qujing Hospital , Qujing 655000 , China

5. School of Life Science, Dali University , Dali 671003 , China

Abstract

Abstract Non-small cell lung cancer (NSCLC) is often driven by mutations in the epidermal growth factor receptor (EGFR) gene. However, rare mutations such as G719X and S768I lack standard anti-EGFR targeted therapies. Understanding the structural differences between wild-type EGFR and these rare mutants is crucial for developing EGFR-targeted drugs. We performed a systematic analysis using molecular dynamics simulations, essential dynamics (ED), molecular mechanics Poisson–Boltzmann surface area, and free energy calculation methods to compare the kinetic properties, molecular motion, and free energy distribution between wild-type EGFR and the rare mutants’ structures G719X-EGFR, S768I-EGFR, and G719X + S768I-EGFR. Our results showed that S768I-EGFR and G719X + S768I-EGFR have higher global and local conformational flexibility and lower thermal and global structural stability than WT-EGFR. ED analysis revealed different molecular motion patterns between S768I-EGFR, G719X + S768I-EGFR, and WT-EGFR. The A-loop and αC-helix, crucial structural elements related to the active state, showed a tendency toward active state development, providing a molecular mechanism explanation for NSCLC caused by EGFR S768I and EGFR G719C + S768I mutations. The present study may be helpful in the development of new EGFR-targeted drugs based on the structure of rare mutations. Our findings may aid in developing new targeted treatments for patients with EGFR S768I and EGFR G719X + S768I mutations.

Publisher

Walter de Gruyter GmbH

Subject

General Agricultural and Biological Sciences,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Neuroscience

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