An analysis of protein folding pathways.
An analysis of protein folding pathways.
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蛋白质折叠途径的分析。
DOI：
10.1021/bi00230a003
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发表时间：
1991
期刊：
影响因子：
2.9
通讯作者：
Unger,R
中科院分区：
文献类型：
--
作者：
Moult,J;Unger,R
我们基于三个基本假设建立了蛋白质折叠过程的模型：疏水性区域的掩埋是构象相对自由能的主要贡献，折叠过程的记录大部分保存在最终结构中，以及变性状态是一个随机卷曲。确定了19种蛋白质结构的详细折叠途径。从这一分析中出现的折叠过程的图像是8-16个残基区域的成核过程之一。然后，成核位通过两种机制导致更大的结构：传播和扩散/碰撞。当传播是主要机制时，使用蒙特卡罗模拟来跟踪折叠路径。因为每种蛋白质都有详细的途径，所以模型很容易进行实验验证。可溶的球形蛋白质在典型的几秒钟时间尺度上折叠成它们的功能结构，至少对于小单体蛋白质来说，没有其他生化机械的帮助(Anfinsen，1970)。因此，原则上可以从氨基酸序列推断出三维结构。蛋白质多肽链可以采用的大量构象阻碍了对所有可能性的调查，并且在自然折叠过程中也提出了一个问题：如果一种蛋白质要通过在构象空间中随机游走来发现其功能构象，则折叠将需要超过1050年(Levinthal，1968)。显然，蛋白质通过利用序列中编码的某种形式的折叠途径来解决这个问题。短链[长达约20个残基(Wetlafer，1973)]可以在不到一秒的时间内搜索所有可能的构象，因此有了折叠的成核或起始点的想法：在折叠过程的早期，往往会采用最终构象的链的较短区域。在成核之后，折叠通常被认为是通过两种机制之一进行的--半稳定成核位的扩散，直到两个或两个以上恰好在折叠状态下发生碰撞，缔合形成下一级结构[扩散/碰撞模型(Karplus&Weaver，1976；Bashford等人，1988)]，或者从成核位生长出结构[传播(Wetlafer，1973)]。熔融的小球变性状态和中间体的实验证据(Kun-ihiro，1989)提供了对折叠过程的不同观点，这里不再进一步考虑。
We have developed a model of the protein folding processbased on three primary assumptions: that burying of hydrophobic area is the dominant contribution to the relative free energy of a conformation, that a record of the folding process is largely preserved in the final structure, and that the denatured state is a random coil. Detailed folding pathways are identified for 19 protein structures. The picture of the folding process that emerges from thisanalysis is one of nucleation by regions of 8-16 residues. Nucleation sites then lead to larger structures by two mechanisms: propagation and diffusion/collision. A Monte Carlo simulation is used to follow the folding pathway when propagation is the dominant mechanism. Because detailed pathways are derived for each protein, the models are susceptible to experimentalverification.Soluble globular proteins fold into their functional structure on a time scale of typically seconds and, at least for small monomeric proteins, without the aid of other biochemical machinery (Anfinsen, 1970). In principle it is therefore possible to deduce the three-dimensional structure from the amino acidsequence. The large number of conformations a protein polypeptide chain can adopt prevents a survey of all the possibilities and poses a problem in the natural folding process too: If a protein is to find its functional conformation by wanderingrandomly through conformational space, in excess of 1050 years would be required for folding (Levinthal, 1968). Proteins solve this problem, apparently, by utilizing some form of folding pathway encoded in the sequence. Short segments of chain [up to about 20 residues long (Wetlaufer, 1973)] can search through all possible confor-mations in less than a second, hence the idea of nucleation or initiation sites for folding: shortregions of chain that will tend to adopt their final conformation early inthe folding process. Following nucleation, folding has generally been supposed to proceed by one of two mechanisms—diffusion of semistable nucleation sites until two or more happen to collide in the folded state, associating to form the next level of structure [the diffusion/collision model (Karplus & Weaver, 1976; Bashford et al., 1988)], or growth of structure out from the nucleation sites [propagation (Wetlaufer, 1973)]. Experimental evidence for molten globule denaturedstates and intermediates (Kun-ihiro, 1989) provide a different view of the folding process, not considered further here.