Department of Applied Physics, Nagoya University, Nagoya 464-8603, Japan.
J Chem Phys. 2011 Mar 28;134(12):125102. doi: 10.1063/1.3565025.
A statistical mechanical model of allosteric transition of proteins is developed by extending the structure-based model of protein folding to cases that a protein has two different native conformations. Partition function is calculated exactly within the model and free-energy surfaces associated with allostery are derived. In this paper, the model of allosteric transition proposed in a previous paper [Proc. Natl. Acad. Sci. U.S.A 134, 7775 (2010)] is reformulated to describe both fluctuation in side-chain configurations and that in backbone structures in a balanced way. The model is applied to example proteins, Ras, calmodulin, and CheY: Ras undergoes the allosteric transition between guanosine diphosphate (GDP)-bound and guanosine triphosphate (GTP)-bound forms, and the model results show that the GDP-bound form is stabilized enough to prevent unnecessary signal transmission, but the conformation in the GTP-bound state bears large fluctuation in side-chain configurations, which may help to bind multiple target proteins for multiple pathways of signaling. The calculated results of calmodulin show the scenario of sequential ordering in Ca(2+) binding and the associated allosteric conformational change, which are realized though the sequential appearing of pre-existing structural fluctuations, i.e., fluctuations to show structures suitable to bind Ca(2+) before its binding. Here, the pre-existing fluctuations to accept the second and third Ca(2+) ions are dominated by the side-chain fluctuation. In CheY, the calculated side-chain fluctuation of Tyr106 is coordinated with the backbone structural change in the β4-α4 loop, which explains the pre-existing Y-T coupling process in this protein. Ability of the model to explain allosteric transitions of example proteins supports the view that the large entropic effects lower the free-energy barrier of allosteric transition.
一个蛋白质变构跃迁的统计力学模型是通过将蛋白质折叠的基于结构的模型扩展到蛋白质具有两种不同天然构象的情况来建立的。在模型中精确地计算了配分函数，并推导出与变构相关的自由能表面。在本文中，重新表述了在以前的一篇论文[Proc. Natl. Acad. Sci. U.S.A 134, 7775 (2010)]中提出的变构跃迁模型，以平衡地描述侧链构象和骨架结构的波动。该模型应用于示例蛋白质 Ras、钙调蛋白和 CheY：Ras 经历了 GDP 结合和 GTP 结合形式的变构跃迁，模型结果表明 GDP 结合形式足够稳定，可以防止不必要的信号传递，但 GTP 结合状态的构象在侧链构象中存在较大波动，这可能有助于与多个靶蛋白结合，用于多条信号通路。钙调蛋白的计算结果显示了 Ca2+结合和相关变构构象变化的顺序排序场景，这是通过预先存在的结构波动的顺序出现来实现的，即波动以显示在 Ca2+结合之前适合结合 Ca2+的结构。在这里，接受第二个和第三个 Ca2+离子的预先存在的波动主要由侧链波动控制。在 CheY 中，计算出的 Tyr106 侧链波动与β4-α4 环中的骨架结构变化协调，这解释了该蛋白中预先存在的 Y-T 耦合过程。该模型解释示例蛋白质变构跃迁的能力支持了这样一种观点，即大的熵效应降低了变构跃迁的自由能势垒。
