Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C,Journal of Chemical Information and Modeling

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Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-11-16 , DOI: 10.1021/acs.jcim.2c01132
Eric R Hantz ₁ , Steffen Lindert ₁

Affiliation

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 wild-type 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.

中文翻译：

心肌肌钙蛋白 C 中潜在钙敏化突变的计算探索和表征

钙依赖性心肌收缩由心肌肌钙蛋白复合物 (cTn) 调节，特别是由其钙结合亚基 (cNTnC) 的 N 末端结构域调节。 cNTnC 含有一个钙结合位点（位点 II），并且对该位点的钙结合改变的研究已经进行了数十年。先前已表明，增加钙敏化的 cNTnC 突变体可能具有治疗益处，例如恢复心肌梗塞事件后的心肌收缩力和功能。在这里，我们通过计算表征了八个突变对 cNTnC 位点 II 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：自适应引导分子动力学（ASMD）和热力学积分（TI）。我们根据所采用的 ASMD 方法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。根据 TI 结果，预测五个突变体会增加位点 II 的钙敏感性。这项研究对两种计算方法进行了有趣的比较，这两种方法都被证明是表征突变 cNTnC 系统中钙敏感性影响的有价值的工具。

更新日期：2022-11-16

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