Intrinsically disordered energy landscapes.
Intrinsically disordered energy landscapes.
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DOI：
10.1038/srep10386
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发表时间：
2015-05-22
影响因子：
4.6
通讯作者：
Wales DJ
中科院分区：
文献类型：
--
作者：
Chebaro Y;Ballard AJ;Chakraborty D;Wales DJ
对本质无序蛋白（IDP）的分析揭示了能源景观的潜在多漏斗结构。我们认为，这种“本质上无序”的景观，以及许多截然不同的竞争性低能量结构，很可能是国内流离失所者的特征，并提供了一种解决其特性的有用方法。特别是，IDP 存在于许多细胞蛋白质相互作用网络中，并且出现了关于它们如何与伴侣结合的几个问题。是否选择与结合结构类似的构象进行结合，或者以诱导拟合方式结合配偶体时是否发生进一步折叠？我们重点关注 p53 上调的细胞凋亡调节剂 (PUMA) 蛋白，该蛋白在与其伴侣结合时采用 β-螺旋构象，并参与细胞凋亡的激活。最近的实验证据表明，折叠对于结合来说不是必需的，并且支持诱导拟合机制。使用各种计算方法，我们推断出 PUMA 肽作为孤立螺旋的不稳定性背后的分子机制。我们发现部分折叠态和螺旋之间存在显着的障碍。我们的结果表明，有利的构象是熔球状，通过带电和疏水接触稳定，其结构类似于平衡状态下相对较少的束缚态。
Analysis of an intrinsically disordered protein (IDP) reveals an underlying multifunnel structure for the energy landscape. We suggest that such ‘intrinsically disordered’ landscapes, with a number of very different competing low-energy structures, are likely to characterise IDPs, and provide a useful way to address their properties. In particular, IDPs are present in many cellular protein interaction networks, and several questions arise regarding how they bind to partners. Are conformations resembling the bound structure selected for binding, or does further folding occur on binding the partner in a induced-fit fashion? We focus on the p53 upregulated modulator of apoptosis (PUMA) protein, which adopts an -helical conformation when bound to its partner, and is involved in the activation of apoptosis. Recent experimental evidence shows that folding is not necessary for binding, and supports an induced-fit mechanism. Using a variety of computational approaches we deduce the molecular mechanism behind the instability of the PUMA peptide as a helix in isolation. We find significant barriers between partially folded states and the helix. Our results show that the favoured conformations are molten-globule like, stabilised by charged and hydrophobic contacts, with structures resembling the bound state relatively unpopulated in equilibrium.
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影响因子：
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