Dynamics and Calcium Association to the N-Terminal Regulatory Domain of Human Cardiac Troponin C: A Multiscale Computational Study

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• 作者：Steffen Lindert ; Peter M. Kekenes-Huskey ; Gary Huber ; Levi Pierce ; J. Andrew McCammon
• 刊名：The Journal of Physical Chemistry B
• 出版年：2012
• 出版时间：July 26, 2012
• 年：2012
• 卷：116
• 期：29
• 页码：8449-8459
• 全文大小：703K
• 年卷期：v.116,no.29(July 26, 2012)
• ISSN：1520-5207

文摘

Troponin C (TnC) is an important regulatory molecule in cardiomyocytes. Calcium binding to site II in TnC initiates a series of molecular events that result in muscle contraction. The most direct change upon Ca²⁺ binding is an opening motion of the molecule that exposes a hydrophobic patch on the surface allowing for Troponin I to bind. Molecular dynamics simulations were used to elucidate the dynamics of this crucial protein in three different states: apo, Ca²⁺-bound, and Ca²⁺-TnI-bound. Dynamics between the states are compared, and the Ca²⁺-bound system is investigated for opening motions. On the basis of the simulations, NMR chemical shifts and order parameters are calculated and compared with experimental observables. Agreement indicates that the simulations sample the relevant dynamics of the system. Brownian dynamics simulations are used to investigate the calcium association of TnC. We find that calcium binding gives rise to correlative motions involving the EF hand and collective motions conducive of formation of the TnI-binding interface. We furthermore indicate the essential role of electrostatic steering in facilitating diffusion-limited binding of Ca²⁺.