Umbrella Sampling Simulations Measure Switch Peptide Binding and Hydrophobic Patch Opening Free Energies in Cardiac Troponin.
Umbrella Sampling Simulations Measure Switch Peptide Binding and Hydrophobic Patch Opening Free Energies in Cardiac Troponin.
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DOI：
10.1021/acs.jcim.2c00508
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发表时间：
2022-11-28
影响因子：
5.6
通讯作者：
Lindert, Steffen
中科院分区：
文献类型：
--
作者：
Cool, Austin M.;Lindert, Steffen
心肌肌钙蛋白复合物（cTn）是心脏收缩的重要调节蛋白。在与Ca 2+结合后，cTn发生构象变化，使肌钙蛋白I转换肽（cTnISP）从肌动蛋白丝释放并与肌钙蛋白C疏水斑块（cTnCHP）结合。该复合物的突变和修饰可改变其对Ca 2+的敏感性，并改变从Ca 2 +-未结合、cTnISP-未结合形式向Ca 2 +-结合、cTnISP-结合形式转变的能量学。我们利用靶向MD（TMD）获得该过渡途径的轨迹，然后通过伞形采样估计与野生型（WT）cTn的cTnISP-cTnCHP结合和cTnCHP打开事件相关的自由能。我们能够重现cTnISP-cTnCHP结合事件的实验值，并获得cTnCHP开放自由能与以前的计算测量较小的cTnC系统。WT cTn的这一优异一致性证明了计算方法在研究cTn复合物的动力学和能量学方面的优势。然后，我们将突变引入到cTn复合物中，导致心肌病或改变其Ca 2+敏感性，并观察到打开cTnCHP的自由能普遍降低。对于这些相同的突变，我们未观察到对cTnISP-cTnCHP结合事件影响的一般趋势。我们的方法为该系统的未来计算研究奠定了基础，该系统预测了尚未表征的突变对cTn动力学和能量学的影响。
The cardiac troponin complex (cTn) is an important regulatory protein in heart contraction. Upon binding of Ca2+, cTn undergoes a conformational shift that allows the troponin I switch peptide (cTnISP) to be released from the actin filament and bind to the troponin C hydrophobic patch (cTnCHP). Mutations and modifications to this complex can change its sensitivity to Ca2+ and alter the energetics of the transition from the Ca2+-unbound, cTnISP-unbound form to the Ca2+-bound, cTnISP-bound form. We utilized targeted MD (TMD) to obtain a trajectory of this transition pathway, followed by umbrella sampling to estimate the free energy associated with the cTnISP-cTnCHP binding and the cTnCHP opening events for wild-type (WT) cTn. We were able to reproduce experimental values for the cTnISP-cTnCHP binding event and obtain cTnCHP opening free energies in agreement with previous computational measurements of smaller cTnC systems. This excellent agreement for WT cTn demonstrated the strength of computational methods in studying the dynamics and energetics of cTn complex. We then introduced mutations to the cTn complex that cause cardiomyopathy or alter its Ca2+-sensitivity and observed a general decrease in the free energy of opening the cTnCHP. For these same mutations, we observed no general trend in the effect on the cTnISP-cTnCHP binding event. Our method sets the stage for future computational studies on this system that predict the consequences of yet uncharacterized mutations on cTn dynamics and energetics.
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影响因子：
5.6
作者：
Bowman, Jacob D.;Coldren, William H.;Lindert, Steffen
通讯作者：
Lindert, Steffen
影响因子：
4.8
作者：
Cheng, Yuanhua;Rao, Vijay;Regnier, Michael
通讯作者：
Regnier, Michael
影响因子：
2.9
作者：
Dong, Wen-Ji;Jayasundar, Jayant James;Cheung, Herbert C.
通讯作者：
Cheung, Herbert C.
DOI：
10.1007/s00249-002-0227-1
发表时间：
2002-07-01
影响因子：
2
作者：
Li, MX;Saude, EJ;Sykes, BD
通讯作者：
Sykes, BD
影响因子：
2.7
作者：
Marston, Steven;Zamora, Juan Eiros
通讯作者：
Zamora, Juan Eiros