SPECIFIC NUCLEUS AS THE TRANSITION-STATE FOR PROTEIN-FOLDING - EVIDENCE FROM THE LATTICE MODEL
SPECIFIC NUCLEUS AS THE TRANSITION-STATE FOR PROTEIN-FOLDING - EVIDENCE FROM THE LATTICE MODEL
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DOI：
10.1021/bi00199a029
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发表时间：
1994-08-23
期刊：
影响因子：
2.9
通讯作者：
SHAKHNOVICH, EI
中科院分区：
文献类型：
--
作者：
ABKEVICH, VI;GUTIN, AM;SHAKHNOVICH, EI
我们研究了晶格模型36聚体蛋白质的折叠机制。利用序列空间中的模拟退火法，我们设计了在给定的靶构象中具有足够低能量的序列，这在我们的研究中起到了天然结构的作用。序列设计算法生成其固有结构是显著的全局能量最小值的序列。然后，对设计的序列进行了折叠的格子蒙特卡罗模拟。在每一次运行中，从随机卷曲构象开始，链达到其自然结构，这表明模型蛋白质解决了莱文塔尔悖论。折叠机制涉及成核生长。一个特定的核的形成，这是一种特定的接触模式，被证明是随后快速折叠到自然状态的必要条件和充分条件。原子核代表了从折叠到熔融球状构象的过渡状态。寻找原子核是折叠的限速步骤，对应于克服主要的自由能障碍。我们还观察到了一条折叠路径，这是在核形成后接近本征状态的过程；这一阶段需要大约1%的模拟时间。核是自然状态的空间局域子结构，具有40个自然接触中的8个。然而，属于核的单体沿序列分散，因此几个核接触是长程的，而另一些是短程的。在较长的链80-mer中也发现了折叠核，它也构成了自然结构的20%。讨论了设计蛋白质折叠的可能机制，以及这项研究的实验意义。
We have studied the folding mechanism of lattice model 36-mer proteins. Using a simulated annealing procedure in sequence space, we have designed sequences to have sufficiently low energy in a given target conformation, which plays the role of the native structure in our study. The sequence design algorithm generated sequences for which the native structures is a pronounced global energy minimum. Then, designed sequences were subjected to lattice Monte Carlo simulations of folding. In each run, starting from a random coil conformation, the chain reached its native structure, which is indicative that the model proteins solve the Levinthal paradox. The folding mechanism involved nucleation growth. Formation of a specific nucleus, which is a particular pattern of contacts, is shown to be a necessary and sufficient condition for subsequent rapid folding to the native state. The nucleus represents a transition state of folding to the molten globule conformation. The search for the nucleus is a rate-limiting step of folding and corresponds to overcoming the major free energy barrier. We also observed a folding pathway that is the approach to the native state after nucleus formation; this stage takes about 1% of the simulation time. The nucleus is a spatially localized substructure of the native state having 8 out of 40 native contacts. However, monomers belonging to the nucleus are scattered along the sequence, so that several nucleus contacts are long-range while other are short-range. A folding nucleus was also found in a longer chain 80-mer, where it also constituted 20% of the native structure. The possible mechanism of folding of designed proteins, as well as the experimental implications of this study is discussed.