Toward Understanding Allosteric Activation of Thrombin: A Conjecture for Important Roles of Unbound Na+ Molecules around Thrombin
Toward Understanding Allosteric Activation of Thrombin: A Conjecture for Important Roles of Unbound Na+ Molecules around Thrombin
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DOI：
10.1021/jp510657n
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发表时间：
2015-03-05
影响因子：
3.3
通讯作者：
Nagaoka, Masataka
中科院分区：
文献类型：
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作者：
Kurisaki, Ikuo;Takayanagi, Masayoshi;Nagaoka, Masataka
我们阐明了未结合的Na+分子在凝血酶的酶促活化中的重要作用。Na+激活凝血酶的分子机制已在变构的背景下进行了讨论。然而，最近的挑战，重新设计K+激活凝血酶显示，变构相互作用是不够的，以解释机制。在这种情况下，我们研究了游离Na+分子在凝血酶-底物结合反应速率最大化中的作用。我们进行了全原子分子动力学（MD）模拟凝血酶在存在三种不同的阳离子; Li+，Na+，和Cs+。虽然这些阳离子通常在凝血酶的S1口袋附近观察到，但较小的阳离子比较大的阳离子分布得更密集和更广泛。这表明了两个观察规则：（i）被Na+包围的凝血酶在缔合反应的初始步骤中处于优势，即，形成相遇复合物系综，以及（ii）Na+分子的存在不一定在缔合反应的最终步骤中具有优势，即，形成立体特异性复合物。总之，我们提出了一个猜想，游离Na+分子也影响凝血酶-底物缔合反应的速率常数最大化，通过最佳地形成一个遇到复杂的合奏。
We shed light on important roles of unbound Na+ molecules in enzymatic activation of thrombin. Molecular mechanism of Na+-activation of thrombin has been discussed in the context of allostery. However, the recent challenge to redesign K+-activated thrombin revealed that the allosteric interaction is insufficient to explain the mechanism. Under these circumstances, we have examined the roles of unbound Na+ molecule in maximization of thrombin-substrate association reaction rate. We performed all-atomic molecular dynamics (MD) simulations of thrombin in the presence of three different cations; Li+, Na+, and Cs+. Although these cations are commonly observed in the vicinity of the S1-pocket of thrombin, smaller cations are distributed more densely and extensively than larger ones. This suggests the two observation rules: (i) thrombin surrounded by Na+ is at an advantage in the initial step of association reaction, namely, the formation of an encounter complex ensemble, and (ii) the presence of Na+ molecules does not necessarily have an advantage in the final step of association reaction, namely, the formation of the stereospecific complex. In conclusion, we propose a conjecture that unbound Na+ molecules also affect the maximization of rate constant of thrombin-substrate association reaction through optimally forming an encounter complex ensemble.