A computational and experimental approach to investigate bepridil binding with cardiac troponin.
A computational and experimental approach to investigate bepridil binding with cardiac troponin.
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研究贝普地尔与心肌肌钙蛋白结合的计算和实验方法。
DOI：
10.1021/jp1094504
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
Li,Yumin
中科院分区：
文献类型：
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作者：
Varughese,JaysonF;Baxley,Tamatha;Chalovich,JosephM;Li,Yumin
心肌肌钙蛋白是心肌收缩的 Ca2+ 依赖性开关，也是心力衰竭治疗药物的潜在靶点。 Bepridil 是一种与肌钙蛋白结合并增加肌肉收缩的钙敏感性的药物。由于贝普地尔已得到充分研究，因此它是通过计算和实验方法进行分析的良好模型。在存在或不存在肌钙蛋白 C N 末端疏水袋内结合的苄普地尔的情况下，对不同大小的肌钙蛋白复合物进行分子动力学 (MD) 模拟。生成了约 100 ns 的模拟轨迹数据，并使用互相关分析以及 MMPBSA 和 MMGBSA 技术进行了分析。结果表明，苯普地尔与心脏 TnC 疏水口袋内的结合降低了 TnC 与 TnI 在 TnC N 结构域和 TnC C 结构域的相互作用，并降低了肌钙蛋白亚基片段之间的运动相关性。使用 MMPBSA 估计的钙结合亲和力表明，bepridil 对分离的 TnC 系统具有敏化作用，但对复合物失去了这种作用。我们对钙解离率的实验测量与该预测一致。我们还观察到，虽然贝普地尔在低钙浓度下增强了肌钙蛋白-原肌球蛋白-肌动蛋白激活的肌球蛋白S1的ATP酶活性，但在高钙浓度下却具有轻微的抑制作用。苯普地尔可增加肌纤维中 ATP 酶的活性和力量的产生，但其效果似乎取决于钙的浓度。
Cardiac troponin is a Ca2+-dependent switch for the contraction in heart muscle and a potential target for drugs in the therapy of heart failure. Bepridil is a drug that binds to troponin and increases calcium sensitivity of muscle contraction. Because bepridil has been well studied, it is a good model for analysis by computational and experimental methods. Molecular dynamics (MD) simulations were performed on troponin complexes of different sizes in the presence and absence of bepridil bound within the hydrophobic pocket at the N-terminal domain of troponin C. About 100 ns of simulation trajectory data were generated, which were analyzed using cross-correlation analyses and MMPBSA and MMGBSA techniques. The results indicated that bepridil binding within the hydrophobic pocket of cardiac TnC decreases the interaction of TnC with TnI at both the N-domain of TnC and the C-domain of TnC, and decreases the correlations of motions among the segments of the troponin subunits. The estimated calcium-binding affinities using MMPBSA showed that bepridil has a sensitizing effect for the isolated system of TnC, but loses this effect for the complex. Our experimental measurements of calcium dissociation rates were consistent with that prediction. We also observed that while bepridil enhanced the troponin−tropomyosin−actin-activated ATPase activity of myosin S1 at low calcium concentrations it was slightly inhibitory at high calcium concentrations. Bepridil increases the ATPase activity and force generation in muscle fibers, but its effects appear to depend on the concentration of calcium.
R.G.Duggleby：“酶学方法”
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