Identification of Allosteric Disulfides from Prestress Analysis
Identification of Allosteric Disulfides from Prestress Analysis
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DOI：
10.1016/j.bpj.2014.06.025
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发表时间：
2014-08-05
影响因子：
3.4
通讯作者：
Graeter, Frauke
中科院分区：
文献类型：
--
作者：
Zhou, Beifei;Baldus, Ilona B.;Graeter, Frauke
二硫键用于在蛋白质结构中的残基之间形成物理交联键，从而稳定蛋白质折叠。除了这种纯粹的结构作用外，它们还可以具有化学活性，参与氧化还原反应，甚至可能充当控制蛋白质功能的变构开关。从二面体键角的独特模式中，已经在静态蛋白质结构中识别出特定类型的二硫键，并且这种键的变构功能被认为与它们存储的扭转应变有关。利用全原子分子动力学模拟方法，对700个二硫键蛋白质进行了模拟，分析了20类二硫键的分子内力。我们发现-RHStaple和-/+RHHook二硫键确实比其他二硫键的应力更大，但应力主要是通过S-S键的伸缩和相邻键角的弯曲来承载的，而不是通过二面体扭转来承载的。这种应力对应于一个类似于200pN的张力值，它被半胱氨酸Cα原子之间的排斥范德华作用所平衡。通过对20,000个静态蛋白质结构的分析，我们证实了S-S键的伸展是-RHStaples和-/+RHHooks的一个普遍特征。考虑到S-S键的强迫拉伸可以加速它们的断裂，我们提出了变构二硫键的预应力有可能改变二硫键的反应性，从而使我们能够很容易地在官能态之间切换。
Disulfide bonds serve to form physical cross-links between residues in protein structures, thereby stabilizing the protein fold. Apart from this purely structural role, they can also be chemically active, participating in redox reactions, and they may even potentially act as allosteric switches controlling protein functions. Specific types of disulfide bonds have been identified in static protein structures from their distinctive pattern of dihedral bond angles, and the allosteric function of such bonds is purported to be related to the torsional strain they store. Using all-atom molecular-dynamics simulations for similar to 700 disulfide bonded proteins, we analyzed the intramolecular mechanical forces in 20 classes of disulfide bonds. We found that two particular classes, the -RHStaple and the -/+RHHook disulfides, are indeed more stressed than other disulfide bonds, but the stress is carried primarily by stretching of the S-S bond and bending of the neighboring bond angles, rather than by dihedral torsion. This stress corresponds to a tension force of magnitude similar to 200 pN, which is balanced by repulsive van der Waals, interactions between the cysteine C alpha atoms. We confirm stretching of the S-S bond to be a general feature of the -RHStaples and the -/+RHHooks by analyzing similar to 20,000 static protein structures. Given that forced stretching of S-S bonds is known to accelerate their cleavage, we propose that prestress of allosteric disulfide bonds has the potential to alter the reactivity of a disulfide, thereby allowing us to readily switch between functional states.