Epidermal growth factor receptor (EGFR) activation is accompanied by dimerization. During the activation of the intracellular kinase domain, two EGFR kinases form an asymmetric dimer, and one side of the dimer (receiver) is activated. Using the string method and Markov state model (MSM), we performed a computational analysis of the structural changes in the activation of the EGFR dimer in this study. The string method reveals the minimum free-energy pathway (MFEP) from the inactive to active structure. The MSM was constructed from numerous trajectories of molecular dynamics simulations around the MFEP, which revealed the free-energy map of structural changes. In the activation of the receiver kinase, the unfolding of the activation loop (A-loop) is followed by the rearrangement of the C-helix, as observed in other kinases. However, unlike other kinases, the free-energy map of EGFR at the asymmetric dimer showed that the active state yielded the highest stability and revealed how interactions at the dimer interface induced receiver activation. As the H-helix of the activator approaches the C-helix of the receiver during activation, the A-loop unfolds. Subsequently, L782 of the receiver enters the pocket between the G- and H-helices of the activator, leading to a rearrangement of the hydrophobic residues around L782 of the receiver, which constitutes a structural rearrangement of the C-helix of the receiver from an outward to an inner position. The MSM analysis revealed long-time scale trajectories via kinetic Monte Carlo.

中文翻译：

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使用弦法和马尔可夫状态模型计算分析二聚化表皮生长因子受体激酶的激活

表皮生长因子受体（EGFR）的激活伴随着二聚化。在细胞内激酶结构域激活过程中，两个EGFR激酶形成不对称二聚体，二聚体的一侧（受体）被激活。在本研究中，我们使用弦法和马尔可夫状态模型（MSM）对EGFR二聚体激活过程中的结构变化进行了计算分析。弦法揭示了从非活性结构到活性结构的最小自由能路径（MFEP）。 MSM 是根据 MFEP 周围的众多分子动力学模拟轨迹构建的，揭示了结构变化的自由能图。在受体激酶的激活过程中，激活环（A 环）展开后，C 螺旋会重新排列，如在其他激酶中观察到的那样。然而，与其他激酶不同，EGFR 在不对称二聚体上的自由能图显示，活性状态产生最高的稳定性，并揭示了二聚体界面上的相互作用如何诱导受体激活。当激活过程中激活剂的 H 螺旋接近受体的 C 螺旋时，A 环展开。随后，受体的L782进入激活剂的G-和H-螺旋之间的口袋，导致受体的L782周围的疏水性残基重排，这构成了受体的C-螺旋的结构重排向外到内部位置。 MSM 分析通过动力学蒙特卡罗揭示了长时间尺度的轨迹。