New Insights to Hydrogen Bonds to Provide Stability in the EGFR Related to Non-small Cell Lung Cancer

Avirup Ghosh, Hong Yan
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Abstract

Lung cancer is the most common cancer in the world, but it is one of the most preventable. Non-small cell lung cancer accounts for approximately 85% of all lung cancers. Epidermal growth factor receptor or EGFR is the class of high-affinity cell surface receptors which are essential in regulating biological processes including cell differentiation, cell survival or death, and cellular metabolism. An amino acid substitution at the 858th position of EGFR, from a Leucine(L) to an Arginine(R) causes L858R mutation within exon 21, which encodes part of the kinase domain and drives to NSCLC. For over 60% of EGFR-muted NSCLC, another mutation T790M can cause drug resistance to erlotinib or gefitinib. In our research work, we considered three structures of EGFR, wild-type, with L858R mutation and with L858R/T790M drug-resistance mutation. The number of hydrogen bond decreases when the EGFR becomes mutated and it reduces even more in its drug-resistance structure. We perform 200 frames of molecular dynamics (MD) simulation to analyze the behavioral changes in hydrogen bonds for all three structures. Since the hydrogen bonds contribute to the conformational stability of the protein and molecular recognition, the knowledge, and results achieved from this study lead to useful insight into the mechanism of NSCLC drug resistance.
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非小细胞肺癌相关EGFR中氢键稳定性的新发现
肺癌是世界上最常见的癌症,但也是最容易预防的癌症之一。非小细胞肺癌约占所有肺癌的85%。表皮生长因子受体(Epidermal growth factor receptor,简称EGFR)是一类高亲和力的细胞表面受体,在调节细胞分化、细胞存活或死亡以及细胞代谢等生物过程中起重要作用。在EGFR的第858个位置,从亮氨酸(L)到精氨酸(R)的氨基酸替换导致外显子21内的L858R突变,该突变编码部分激酶结构域并驱动NSCLC。对于超过60%的egfr沉默的NSCLC,另一种突变T790M可引起对厄洛替尼或吉非替尼的耐药。在我们的研究工作中,我们考虑了三种结构的EGFR,野生型,L858R突变和L858R/T790M耐药突变。当EGFR发生突变时,氢键的数量减少,其耐药结构的减少幅度更大。我们进行了200帧分子动力学(MD)模拟来分析这三种结构的氢键行为变化。由于氢键有助于蛋白质的构象稳定性和分子识别,因此本研究获得的知识和结果有助于深入了解NSCLC耐药机制。
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