通过分子动力学模拟和 MM-PBSA 计算探索 EGFR 与磷酸化 Mig6 的相互作用。
Exploring the interactions of EGFR with phosphorylated Mig6 by molecular dynamics simulations and MM-PBSA calculations.
机构信息
Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, Jilin University, Changchun 130023, People's Republic of China.
Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, Jilin University, Changchun 130023, People's Republic of China; Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130023, People's Republic of China.
出版信息
J Theor Biol. 2018 Jun 14;447:118-125. doi: 10.1016/j.jtbi.2018.03.028. Epub 2018 Mar 21.
Mig6, a negative regulator, directly binds to epidermal growth factor receptor (EGFR), including Mig6-segment1 and Mig6-segment2. Mig6 requires phosphorylation of Y394 on Mig6-segment2 in order to inhibit EGFR. Two phosphorylation pathways for Y394 have been previously reported and the first way may phosphorylate Y394 primed by Y395 phosphorylation. Besides, the binding mechanism of phosphorylated Mig6-segment2 with EGFR has not been elucidated clearly. Focused on EGFR complex with phosphorylated Mig6-segment2, molecular dynamics (MD) simulations were performed to explore the interactions of Mig6-segment2 with EGFR. Our results indicate a probable phosphorylation pathway on Y394 and some key residues of EGFR play important roles in binding to phosphorylated Mig6-segment2. In addition, a special L-shaped structure was found to be possibly associated with irreversible inhibition of EGFR by Mig6. Our work can give meaningful information to better understand the phosphorylation pathways for Y394 and the interactions of EGFR binding to phosphorylated Mig6-segment2.
Mig6 是一种负调控因子，可直接与表皮生长因子受体（EGFR）结合，包括 Mig6 片段 1 和 Mig6 片段 2。Mig6 需要 Mig6 片段 2 上的 Y394 磷酸化才能抑制 EGFR。此前已经报道了两种 Y394 的磷酸化途径，第一种途径可能是由 Y395 磷酸化引发的磷酸化。此外，磷酸化的 Mig6 片段 2 与 EGFR 的结合机制尚未阐明。本研究针对与磷酸化 Mig6 片段 2 结合的 EGFR 复合物，进行了分子动力学（MD）模拟，以探索 Mig6 片段 2 与 EGFR 的相互作用。我们的结果表明 Y394 上可能存在一种磷酸化途径，EGFR 的一些关键残基在与磷酸化 Mig6 片段 2 结合中发挥重要作用。此外，还发现了一种特殊的 L 形结构，可能与 Mig6 对 EGFR 的不可逆抑制有关。我们的工作可以为更好地理解 Y394 的磷酸化途径和 EGFR 与磷酸化 Mig6 片段 2 的相互作用提供有意义的信息。
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