Conformational Transition Pathways of Epidermal Growth Factor Receptor Kinase Domain from Multiple Molecular Dynamics Simulations and Bayesian Clustering.
Conformational Transition Pathways of Epidermal Growth Factor Receptor Kinase Domain from Multiple Molecular Dynamics Simulations and Bayesian Clustering.
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多分子动力学模拟和贝叶斯聚类的表皮生长因子受体激酶结构域的构象转变途径
DOI：
10.1021/ct500162b
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发表时间：
2014-08-12
影响因子：
5.5
通讯作者：
Dong, Zigang
中科院分区：
文献类型：
--
作者：
Li, Yan;Li, Xiang;Ma, Weiya;Dong, Zigang
表皮生长因子受体（EGFR）在多种癌细胞中被异常激活，是癌症治疗的重要靶点。深入了解EGFR在活性和非活性状态之间的构象变化具有药学意义。在这里，我们提出了一个策略相结合的多靶向分子动力学模拟，无偏分子动力学模拟，贝叶斯聚类研究过渡途径在激活/失活过程中的EGFR激酶结构域。两个不同的途径之间的活动和非活动形式的设计，探索和比较。基于贝叶斯聚类和粗糙的二维自由能表面，能量有利的途径被识别，虽然DFG翻转发生在两个途径。此外，在我们的模拟中出现了另一种具有不同中间态的途径。不同途径的比较还表明，Lys 745-Glu 762相互作用的破坏在DFG翻转中至关重要，而A环的移动显着促进了构象变化。我们的模拟产生新的见解EGFR构象转变。此外，我们的研究结果验证了这种方法是有效的和有效的蛋白质构象变化的采样和不同的途径的比较。
The epidermal growth factor receptor (EGFR) is aberrantly activated in various cancer cells and an important target for cancer treatment. Deep understanding of EGFR conformational changes between the active and inactive states is of pharmaceutical interest. Here we present a strategy combining multiply targeted molecular dynamics simulations, unbiased molecular dynamics simulations, and Bayesian clustering to investigate transition pathways during the activation/inactivation process of EGFR kinase domain. Two distinct pathways between the active and inactive forms are designed, explored, and compared. Based on Bayesian clustering and rough two-dimensional free energy surfaces, the energy-favorable pathway is recognized, though DFG-flip happens in both pathways. In addition, another pathway with different intermediate states appears in our simulations. Comparison of distinct pathways also indicates that disruption of the Lys745-Glu762 interaction is critically important in DFG-flip while movement of the A-loop significantly facilitates the conformational change. Our simulations yield new insights into EGFR conformational transitions. Moreover, our results verify that this approach is valid and efficient in sampling of protein conformational changes and comparison of distinct pathways.
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影响因子：
6.8
作者：
Grant BJ;Gorfe AA;McCammon JA
通讯作者：
McCammon JA
影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
DOI：
10.1073/pnas.0914540107
发表时间：
2010-03-16
影响因子：
11.1
作者：
Abrams, Cameron F.;Vanden-Eijnden, Eric
通讯作者：
Vanden-Eijnden, Eric
影响因子：
56.9
作者：
Grubmuller, H;Heymann, B;Tavan, P
通讯作者：
Tavan, P
影响因子：
5.7
作者：
Gajiwala, Ketan S.;Feng, Junli;Stewart, Al
通讯作者：
Stewart, Al