Destruction of long-range interactions by a single mutation in lysozyme
Destruction of long-range interactions by a single mutation in lysozyme
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DOI：
10.1073/pnas.0701249104
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发表时间：
2007-04-03
影响因子：
11.1
通讯作者：
Berne, Bruce J.
中科院分区：
文献类型：
--
作者：
Zhou, Ruhong;Eleftheriou, Maria;Berne, Bruce J.
基于a>；=10亩S分子动力学模拟，我们提出了一个单一突变(W62G)导致蛋清溶菌酶惊人错误折叠的机制。我们对野生型和突变型溶菌酶在生物温度(pH 2和7)下8M尿素溶液中的模拟表明，突变型结构比野生型溶菌酶更不稳定，突变体表现出更大的波动和更少的天然接触。对局部接触的分析表明，Trp-62残基是野生型内部合作远程相互作用的关键，在野生型中，它就像两个相邻的碱性残基之间的桥梁。因此，在野生型中，在这些残基附近可以形成一个类似天然的簇或成核位点，但在突变体中则不能。二级结构的时间演化也显示出突变体比野生型更快地损失β-折叠，而在8M尿素中，野生型和突变体的一些α-螺旋在整个模拟过程中都持续存在(尽管三级结构基本上都消失了)。这些发现支持Dobson和他的同事[Klein-Seetharam J，Oikama M，Grimshaw SB，Wirmer J，Duchardt E，Ueda T，Imoto T，Smith U，Dobson CM，Schwalbe H(2002)Science 295：1719-1722]最近的实验研究的一般结论，提供了错误折叠机制的详细但不同的分子图像。
We propose a mechanism, based on a >= 10-mu s molecular dynamics simulation, for the surprising misfolding of hen egg-white lysozyme caused by a single mutation (W62G). Our simulations of the wild-type and mutant lysozymes in 8 M urea solution at biological temperature (with both pH 2 and 7) reveal that the mutant structure is much less stable than that of the wild type, with the mutant showing larger fluctuations and less native-like contacts. Analysis of local contacts reveals that the Trp-62 residue is the key to a cooperative long-range interaction within the wild type, where it acts like a bridge between two neighboring basic residues. Thus, a native-like cluster or nucleation site can form near these residues in the wild type but not in the mutant. The time evolution of the secondary structure also exhibits a quicker loss of the beta-sheets in the mutant than in the wild type, whereas some of the alpha-helices persist during the entire simulation in both the wild type and the mutant in 8 M urea (even though the tertiary structures are basically all gone). These findings, while supporting the general conclusions of a recent experimental study by Dobson and coworkers [Klein-Seetharam J, Oikama M, Grimshaw SB, Wirmer J, Duchardt E, Ueda T, Imoto T, Smith U, Dobson CM, Schwalbe H (2002) Science 295:1719-1722], provide a detailed but different molecular picture of the misfolding mechanism.