Trifluoperazine regulation of calmodulin binding to Fas: a computational study.
Trifluoperazine regulation of calmodulin binding to Fas: a computational study.
复制标题
三氟拉嗪对钙调蛋白与 Fas 结合的调节：一项计算研究。
作者：
Pan,Di;Yan,Qi;Chen,Yabing;McDonald,JayM;Song,Yuhua
死亡诱导信号复合体(DISC)的形成是Fas介导的细胞凋亡信号传递的关键步骤。已有实验证明钙调素(CaM)拮抗剂三氟拉嗪(TFP)可调节CaM-Fas结合并影响Fas介导的视盘形成。在本研究中，我们结合分子动力学模拟和结合自由能分析，从结构和热力学两个角度研究了TFP与CaM结合的反协同特性以及TFP对CaM-Fas相互作用的影响。我们研究了不同数量的TFP分子与CaM的相互作用，并探讨了CaM构象变化对CaM-Fas结合的影响。这些分析结果表明，与CaM结合的TFP分子的数量直接影响CaM的α-螺旋的形成和α-螺旋内的氢键占据，从而导致CaM的构象和运动的变化。这些变化影响了CaM与Fas的结合，导致Fas的二级结构变化，以及CaM-Fas复合体中Fas的构象和运动的变化，潜在地扰乱了Fas相关死亡结构域的募集以形成椎间盘。本研究的计算结果揭示了CaM拮抗剂TFP以浓度依赖的方式调节CaM-Fas结合和Fas介导的视盘形成的结构和分子机制。蛋白质2011；©2011 Wiley-Liss，Inc.
Death‐inducing signaling complex (DISC) formation is a critical step in Fas‐mediated signaling for apoptosis. Previous experiments have demonstrated that the calmodulin (CaM) antagonist, trifluoperazine (TFP) regulates CaM‐Fas binding and affects Fas‐mediated DISC formation. In this study, we investigated the anti‐cooperative characteristics of TFP binding to CaM and the effect of TFP on the CaM‐Fas interaction from both structural and thermodynamic perspectives using combined molecular dynamics simulations and binding free energy analyses. We studied the interactions of different numbers of TFP molecules with CaM and explored the effects of the resulting conformational changes in CaM on CaM‐Fas binding. Results from these analyses showed that the number of TFP molecules bound to CaM directly influenced α‐helix formation and hydrogen bond occupancy within the α‐helices of CaM, contributing to the conformational and motion changes in CaM. These changes affected CaM binding to Fas, resulting in secondary structural changes in Fas and conformational and motion changes of Fas in CaM‐Fas complexes, potentially perturbing the recruitment of Fas‐associated death domain for DISC formation. The computational results from this study reveal the structural and molecular mechanisms that underlie the role of the CaM antagonist, TFP, in regulation of CaM‐Fas binding and Fas‐mediated DISC formation in a concentration‐dependent manner. Proteins 2011; © 2011 Wiley‐Liss, Inc.