2’-deoxy-ATP (dATP) improves cardiac function by increasing the rate of crossbridge cycling and Ca 2 + transient decay. However, the mechanisms of these effects and how therapeutic responses to dATP are achieved when dATP is only a small fraction of the total ATP pool remain poorly understood. Here, we used a multiscale computational modeling approach to analyze the mechanisms by which dATP improves ventricular function. We integrated atomistic simulations of prepowerstroke myosin and actomyosin association, filament-scale Markov state modeling of sarcomere mechanics, cell-scale analysis of myocyte Ca 2 + dynamics and contraction, organ-scale modeling of biventricular mechanoenergetics, and systems level modeling of circulatory dynamics. Molecular and Brownian dynamics simulations showed that dATP increases the actomyosin association rate by 1.9 fold. Markov state models predicted that dATP increases the pool of myosin heads available for crossbridge cycling, increasing steady-state force development at low dATP fractions by 1.3 fold due to mechanosensing and nearest-neighbor cooperativity. This was found to be the dominant mechanism by which small amounts of dATP can improve contractile function at myofilament to organ scales. Together with faster myocyte Ca 2 + handling, this led to improved ventricular contractility, especially in a failing heart model in which dATP increased ejection fraction by 16% and the energy efficiency of cardiac contraction by 1%. This work represents a complete multiscale model analysis of a small molecule myosin modulator from single molecule to organ system biophysics and elucidates how the molecular mechanisms of dATP may improve cardiovascular function in heart failure with reduced ejection fraction.

中文翻译：

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多尺度模型显示 2'-脱氧-ATP 如何挽救心力衰竭的心室功能


2'-脱氧-ATP (dATP) 通过增加桥循环速率和 Ca 2 + 瞬时衰减来改善心脏功能。然而，这些作用的机制以及当 dATP 仅占总 ATP 池的一小部分时如何实现对 dATP 的治疗反应仍然知之甚少。在这里，我们使用多尺度计算建模方法来分析 dATP 改善心室功能的机制。我们集成了中风前肌球蛋白和肌动球蛋白关联的原子模拟、肌节力学的细丝尺度马尔可夫状态建模、肌细胞 Ca 2 + 动力学和收缩的细胞尺度分析、双心室机械能学的器官尺度建模以及循环动力学的系统级建模。分子和布朗动力学模拟表明，dATP 使肌动球蛋白结合率提高了 1.9 倍。马尔可夫状态模型预测，dATP 增加了可用于横桥循环的肌球蛋白头池，由于机械传感和最近邻协同作用，低 dATP 分数下的稳态力发展增加了 1.3 倍。这被发现是少量 dATP 可以改善肌丝到器官尺度的收缩功能的主要机制。与更快的心肌细胞 Ca 2+ 处理一起，这导致了心室收缩力的改善，特别是在衰竭的心脏模型中，dATP 使射血分数增加了 16%，心脏收缩的能量效率增加了 1%。这项工作代表了对小分子肌球蛋白调节剂从单分子到器官系统生物物理学的完整多尺度模型分析，并阐明了 dATP 的分子机制如何改善射血分数降低的心力衰竭患者的心血管功能。