Factors governing the protonation state of cysteines in proteins: An ab initio/CDM study
Factors governing the protonation state of cysteines in proteins: An ab initio/CDM study
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DOI：
10.1021/ja012620l
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发表时间：
2002-06-12
影响因子：
15
通讯作者：
Lim, C
中科院分区：
文献类型：
--
作者：
Dudev, T;Lim, C
金属与半胱氨酸结合的详细机制尚不清楚。目前尚不清楚是否每种金属阳离子都能诱导半胱氨酸去质子化，电介质如何影响这一过程，以及金属第一和第二配位壳的其他配体在多大程度上影响半胱氨酸电离。锌阳离子的正电荷被前两个结合的半胱氨酸的电荷转移所减少，是否仍然可以帮助Cys(3)His和Cys(4)锌指核中下一个或两个半胱氨酸的去质子化还不清楚。在这里，我们阐明了控制金属结合位点，特别是锌的半胱氨酸质子化状态的因素。CYS4配合物，使用联合从头算和连续介质方法。预计过渡金属指示物如Zn2+和Cu2+以及三价阳离子如Al3+具有明显的接受带负电荷的Cys-电荷的能力，可以诱导半胱氨酸氯旋化，但“硬”二价阳离子如Mg2+则不能。高介电介质有利于半胱氨酸去质子化，而低介电介质有利于质子化。研究发现，金属第一壳层中的极化配体可以竞争性地向金属阳离子提供电荷，从而降低金属辅助半胱氨酸去质子化的效率。计算结果表明，在Cys(4)锌指核和[Zn]的折叠过程中，锌离子有助于所有半胱氨酸的去质子化。（CYS-）(4)]（2-）状态很可能保留在蛋白质的最终折叠构象中，前提是结合位点被主肽基或赖氨酸/精氨酸侧链紧密包裹，从而稳定电离的半胱氨酸核心。
The detailed mechanism of metal-cysteine binding is still poorly understood. It is not clear if every metal cation can induce cysteine deprotonation, how the dielectric medium affects this process, and the extent to which other ligands from the metal's first and second coordination shell influence cysteine ionization. It is also not clear if the zinc cation, with its positive charge reduced by charge transfer from the first two bound cysteinates, could still assist deprotonation of the next one or two cysteines in Cys(3)His and Cys(4) zinc-finger cores. Here, we elucidate the factors governing the cysteine protonation state in metal-binding sites, in particular in Zn.CYS4 complexes, using a combined ab initio and continuum dielectric approach. Transition metal dications such as Zn2+ and Cu2+ and trivalent cations such as Al3+ with pronounced ability to accept charge from negatively charged Cys- are predicted to induce cysteine cleprotonation, but not "hard" divalent cations such as Mg2+. A high dielectric medium was found to favor cysteine deprotonation, while a low one favored the protonated state. Polarizable ligands in the metal's first shell that can competitively donate charge to the metal cation were found to lower the efficiency of the metal-assisted cysteine deprotonation. The calculations predict that the zinc cation could assist deprotonation of all the cysteines during the folding of Cys(4) Zinc-finger cores and the [Zn.(CYS-)(4)](2-) state is likely to be preserved in the final folded conformation of the protein provided the binding site is tightly encapsulated by backbone peptide groups or lysine/arginine side chains, which stabilize the ionized cysteine core.