A multiscale computational approach to dissect early events in the erb family receptor mediated activation, differential signaling, and relevance to oncogenic transformations
A multiscale computational approach to dissect early events in the erb family receptor mediated activation, differential signaling, and relevance to oncogenic transformations
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DOI：
10.1007/s10439-006-9251-0
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发表时间：
2007-06-01
影响因子：
3.8
通讯作者：
Radhakrishnan, Ravi
中科院分区：
文献类型：
--
作者：
Liu, Yingting;Purvis, Jeremy;Radhakrishnan, Ravi
我们描述了一个分层的多尺度计算方法的基础上的分子动力学模拟，基于自由能的分子对接模拟，确定性网络为基础的动力学建模，和混合离散/连续随机动力学协议，研究二聚体介导的受体激活特性的Erb家族受体，特别是表皮生长因子受体（EGFR）。通过这些建模方法，我们能够通过考虑特定的EGFR酪氨酸激酶（EGFRTK）对接介导的RTK尾上的不同C-末端肽酪氨酸的差异结合和磷酸化的相互作用，扩展EGF介导的信号转导的先前建模。通过模拟通过在分子基础上解析的EGFRTK分支途径的信号流，我们能够转录受体中分子改变的影响（例如，受体的突变形式）与不同的动力学行为和下游信号应答的关系。我们的分子动力学模拟表明，药物敏感突变（L 834 R）的EGFR稳定的活性构象，使系统的组成型活性。对接模拟显示了抑制剂结合的优先特征（野生型与突变型受体）以及特定底物酪氨酸的磷酸化相对于其他底物的优先增强。我们发现，与野生型系统相比，L 834 R突变体RTK优先结合抑制剂厄洛替尼，以及优先磷酸化底物酪氨酸Y1068，但不磷酸化Y1173。我们预测，这些分子水平的变化导致优先激活Akt信号通路相比，Erk信号通路的细胞与正常的EGFR表达。对于EGFR过表达的细胞，与野生型相比，突变体过度激活Erk和Akt途径。这些结果与文献中报道的定性实验测量结果一致。我们讨论了这些后果的网络拓扑结构和信号特征的改变（突变）细胞系的形状不同的关系，天然细胞系。
We describe a hierarchical multiscale computational approach based on molecular dynamics simulations, free energy-based molecular docking simulations, deterministic network-based kinetic modeling, and hybrid discrete/continuum stochastic dynamics protocols to study the dimer-mediated receptor activation characteristics of the Erb family receptors, specifically the epidermal growth factor receptor (EGFR). Through these modeling approaches, we are able to extend the prior modeling of EGF-mediated signal transduction by considering specific EGFR tyrosine kinase (EGFRTK) docking interactions mediated by differential binding and phosphorylation of different C-terminal peptide tyrosines on the RTK tail. By modeling signal flows through branching pathways of the EGFRTK resolved on a molecular basis, we are able to transcribe the effects of molecular alterations in the receptor (e.g., mutant forms of the receptor) to differing kinetic behavior and downstream signaling response. Our molecular dynamics simulations show that the drug sensitizing mutation (L834R) of EGFR stabilizes the active conformation to make the system constitutively active. Docking simulations show preferential characteristics (for wildtype vs. mutant receptors) in inhibitor binding as well as preferential enhancement of phosphorylation of particular substrate tyrosines over others. We find that in comparison to the wildtype system, the L834R mutant RTK preferentially binds the inhibitor erlotinib, as well as preferentially phosphorylates the substrate tyrosine Y1068 but not Y1173. We predict that these molecular level changes result in preferential activation of the Akt signaling pathway in comparison to the Erk signaling pathway for cells with normal EGFR expression. For cells with EGFR over expression, the mutant over activates both Erk and Akt pathways, in comparison to wildtype. These results are consistent with qualitative experimental measurements reported in the literature. We discuss these consequences in light of how the network topology and signaling characteristics of altered (mutant) cell lines are shaped differently in relationship to native cell lines.