Retinal conformation governs pKa of protonated Schiff base in rhodopsin activation.
Retinal conformation governs pKa of protonated Schiff base in rhodopsin activation.
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DOI：
10.1021/ja4002986
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发表时间：
2013-06-26
影响因子：
15
通讯作者：
Feller, Scott E.
中科院分区：
文献类型：
--
作者：
Zhu, Shengshuang;Brown, Michael F.;Feller, Scott E.
我们已经探讨了构象能量学和质子化状态的席夫碱在视网膜，共价结合的配体负责激活G蛋白偶联受体视紫红质，使用量子化学计算之间的关系。在这个系统上的实验结构测定和大规模分子模拟的指导下，我们研究了视网膜多烯链中每个键的旋转，分别代表黑暗和光活化状态的质子化和去质子化状态。特别注意的是扭转自由度，决定了分子的形状，因此它与蛋白质结合口袋的相互作用。虽然retinal中的大多数扭转自由度的特征在于在生理温度下使结构波动最小化的大的能量势垒，但限定β-紫罗兰酮环与多烯链的相对取向的C6-C7二面角具有适度的势垒高度和随着席夫碱的质子化而显著变化的扭转能量表面。构象自由度和质子化状态之间的这种令人惊讶的耦合通过计算作为C6-C7二面角的函数的pKa来进一步量化。值得注意的是，大于两个单位的pKa位移产生的扭转波动中观察到的分子动力学模拟的完整的配体-蛋白质-膜系统。由此可见，希夫碱的质子化状态的波动在形成活化的MII状态之前发生。这些新的结果揭示了视网膜构象变化的重要机制方面，参与视紫红质在视觉过程中的激活。
We have explored the relationship between conformational energetics and the protonation state of the Schiff base in retinal, the covalently bound ligand responsible for activating the G protein–coupled receptor rhodopsin, using quantum chemical calculations. Guided by experimental structural determinations and large-scale molecular simulations on this system, we examined rotation about each bond in the retinal polyene chain, for both the protonated and deprotonated states that represent the dark and photoactivated states, respectively. Particular attention was paid to the torsional degrees of freedom that determine the shape of the molecule, and hence its interactions with the protein binding pocket. While most torsional degrees of freedom in retinal are characterized by large energetic barriers that minimize structural fluctuations under physiological temperatures, the C6–C7 dihedral defining the relative orientation of the β-ionone ring to the polyene chain has both modest barrier heights, and a torsional energy surface that changes dramatically with protonation of the Schiff base. This surprising coupling between conformational degrees of freedom and protonation state is further quantified by calculations of the pKa as a function of the C6–C7 dihedral angle. Notably, pKa shifts of greater than two units arise from torsional fluctuations observed in molecular dynamics simulations of the full ligand-protein-membrane system. It follows that fluctuations in the protonation state of the Schiff base occur prior to forming the activated MII state. These new results shed light on important mechanistic aspects of retinal conformational changes that are involved in the activation of rhodopsin in the visual process.
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影响因子：
64.8
作者：
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通讯作者：
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影响因子：
3.3
作者：
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影响因子：
3.4
作者：
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影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
DOI：
10.1073/pnas.0701732104
发表时间：
2007-05-08
影响因子：
11.1
作者：
Frutos, Luis Manuel;Andruniow, Tadeusz;Olivucci, Massimo
通讯作者：
Olivucci, Massimo