Protein folding through kinetic discrimination
Protein folding through kinetic discrimination
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DOI：
10.1021/ja070386e
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发表时间：
2007-07-11
影响因子：
15
通讯作者：
Linse, Bjorn
中科院分区：
文献类型：
--
作者：
Linse, Sara;Linse, Bjorn
蛋白质在μ s-ms时间尺度上折叠。然而，多肽骨架的可能构象的数量是如此之大，以至于随机抽样不允许蛋白质在宇宙的生命周期内折叠，即莱文塔尔悖论。我们在这里表明，蛋白质链可以折叠，如果平均原生接触生存时间比非原生的，也就是说，如果解离速率常数接触断裂是低于原生的比非原生的相互作用的高保真度。这一发现的一个重要结果是，蛋白质折叠不需要特定的途径。相反，形成的接触之间的动力学歧视是折叠进行到天然状态的充分标准。成功的蛋白质折叠需要生产性接触存活足够长的时间，以获得一定程度的概率，在第一个相互作用单元解离之前形成其他天然接触。如果原生接触比非原生接触存活更长时间，这可以防止错误折叠，并为折叠过程提供朝向原生状态的方向性。如果平均而言，所有接触都存活同样长的时间，则认为蛋白质链通过随机搜索所有可能的构象而折叠（即，Levinthal paradox）。一个适度的程度的协同性之间的原生接触，即，相邻的接触，降低解离速率，转移到一个现实的制度所需的比率的解离速率，并使折叠的随机过程与成核步骤。没有动力学歧视需要调用关于的关联过程，这是建模为依赖于链段的扩散速率。
Proteins fold on a mu s-ms time scale. However, the number of possible conformations of the polypeptide backbone is so large that random sampling would not allow the protein to fold within the lifetime of the universe, the Levinthal paradox. We show here that a protein chain can fold efficiently with high fidelity if on average native contacts survive longer than non-native ones, that is, if the dissociation rate constant for breakage of a contact is lower for native than for non-native interactions. An important consequence of this finding is that no pathway needs to be specified for a protein to fold. Instead, kinetic discrimination among formed contacts is a sufficient criterion for folding to proceed to the native state. Successful protein folding requires that productive contacts survive long enough to obtain a certain level of probability that other native contacts form before the first interacting unit dissociates. If native contacts survive longer than non-native ones, this prevents misfolding and provides the folding process with directionality toward the native state. If on average all contacts survive equally long, the protein chain is deemed to fold through random search through all possible conformations (i.e., the Levinthal paradox). A modest degree of cooperativity among the native contacts, that is, decreased dissociation rate next to neighboring contacts, shifts the required ratio of dissociation rates into a realistic regime and makes folding a stochastic process with a nucleation step. No kinetic discrimination needs to be invoked in regards to the association process, which is modeled as dependent on the diffusion rate of chain segments.