Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C.
Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C.
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DOI：
10.1021/acs.jcim.2c01132
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发表时间：
2022-12-12
影响因子：
5.6
通讯作者：
Lindert, Steffen
中科院分区：
文献类型：
--
作者：
Hantz, Eric R.;Lindert, Steffen
钙依赖性心肌收缩受心肌肌钙蛋白复合物（cTn）调节，特别是受其钙结合亚基（cNTnC）的N-末端结构域调节。cNTnC含有一个钙结合位点（位点II），该位点的钙结合改变已经研究了几十年。先前已经表明，增加钙致敏的cNTnC突变体可能具有治疗益处，例如在心肌梗死事件后恢复心肌收缩性和功能。在这里，我们计算的特点是8个突变对cNTnC位点II的钙结合亲和力的潜在影响。我们利用两种不同的方法来估计钙结合：自适应导向分子动力学（ASMD）和热力学积分（TI）。基于所采用的ASMD方法，我们观察到所有突变的致敏趋势。TI结果显示与野生型cNTnC中实验已知的钙结合亲和力非常一致。基于TI结果，预测5个突变体增加位点II的钙敏感性。这项研究提出了一个有趣的比较两种计算方法，这两种方法都已被证明是有价值的工具，在突变cNTnC系统中的钙敏感性的影响特征。
Calcium-dependent heart muscle contraction is regulated by the cardiac troponin protein complex (cTn), and specifically by the N-terminal domain of its calcium binding subunit (cNTnC). cNTnC contains one calcium binding site (site II), and altered calcium binding in this site has been studied for decades. It has been previously shown that cNTnC mutants which increase calcium sensitization may have therapeutic benefits, such as restoring cardiac muscle contractility and functionality post myocardial infarction events. Here we computationally characterized eight mutations for their potential effects on calcium binding affinity in site II of cNTnC. We utilized two distinct methods to estimate calcium binding: adaptive steered molecular dynamics (ASMD) and thermodynamic integration (TI). We observed a sensitizing trend for all mutations based on the employed ASMD methodology. The TI results showed excellent agreement with experimentally known calcium binding affinities in wildtype cNTnC. Based on the TI results, five mutants were predicted to increase calcium sensitivity in site II. This study presents an interesting comparison of the two computational methods, which have both been shown to be valuable tools in characterizing the impacts of calcium sensitivity in mutant cNTnC systems.
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作者：
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通讯作者：
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影响因子：
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通讯作者：
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