Investigation of the Recovery Stroke and ATP Hydrolysis and Changes Caused Due to the Cardiomyopathic Point Mutations in Human Cardiac β Myosin.
Investigation of the Recovery Stroke and ATP Hydrolysis and Changes Caused Due to the Cardiomyopathic Point Mutations in Human Cardiac β Myosin.
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DOI：
10.1021/acs.jpcb.1c03144
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发表时间：
2021-06-24
期刊：
影响因子：
--
通讯作者：
Schwartz SD
中科院分区：
文献类型：
--
作者：
Chakraborti A;Baldo AP;Tardiff JC;Schwartz SD
人心脏β肌球蛋白经历作为心肌力产生机制的一部分的过桥循环。恢复冲程被认为是动力学循环的关键步骤之一，因为它是定位ATP水解和与肌动蛋白相互作用的活性位点残基所需的构象重排。我们探索了过渡的自由能表面，并研究了遗传性心肌病引起的突变R453C，I457T和I467T对这一步的影响。这项工作扩展了以前的研究Dictyosteelium myosin II与工程突变。在这里，像以前一样，我们生成了一个无偏的热力学系综的反应轨迹的化学步骤使用过渡路径采样。我们的方法能够预测恢复性中风的动力学变化，以及预测ATP分解为ADP和HPO 42 −的途径，并稳定偏磷酸盐中间体。我们还观察到网骨藻肌球蛋白II和人心脏β肌球蛋白在ATP水解方面的明显差异，并预测了突变I467T对化学步骤的影响。
Human cardiac β myosin undergoes the crossbridge cycle as part of the force-generating mechanism of cardiac muscle. The recovery stroke is considered one of the key steps of the kinetic cycle as it is the conformational rearrangement required to position the active site residues for hydrolysis of ATP and interaction with actin. We explored the free-energy surface of the transition and investigated the effect of the genetic cardiomyopathy causing mutations R453C, I457T, and I467T on this step using metadynamics. This work extends previous studies on Dictyostelium myosin II with engineered mutations. Here, like previously, we generated an unbiased thermodynamic ensemble of reactive trajectories for the chemical step using transition path sampling. Our methodologies were able to predict the changes to the dynamics of the recovery stroke as well as predict the pathway of breakdown of ATP to ADP and HPO42− with the stabilization of the metaphosphate intermediate. We also observed clear differences between the Dictyostelium myosin II and human cardiac β myosin for ATP hydrolysis as well as predict the effect of the mutation I467T on the chemical step.
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DOI：
10.1073/pnas.1809540115
发表时间：
2018-08-28
影响因子：
11.1
作者：
Anderson, Robert L.;Trivedi, Darshan V.;Spudich, James A.
通讯作者：
Spudich, James A.
影响因子：
3.3
作者：
Li, GH;Cui, Q
通讯作者：
Cui, Q
影响因子：
2.9
作者：
LYMN, RW;TAYLOR, EW
通讯作者：
TAYLOR, EW
影响因子：
2.9
作者：
Lu, Xiya;Ovchinnikov, Victor;Cui, Qang
通讯作者：
Cui, Qang
影响因子：
5.7
作者：
Koppole, Sampath;Smith, Jeremy C.;Fischer, Stefan
通讯作者：
Fischer, Stefan