Linse Sara, Linse Björn
Biophysical Chemistry, Lund University, Chemical Centre, PO Box 124, SE-221 00 Lund, Sweden.
J Am Chem Soc. 2007 Jul 11;129(27):8481-6. doi: 10.1021/ja070386e. Epub 2007 Jun 12.
Proteins fold on a micros-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.
蛋白质在微秒到毫秒的时间尺度上折叠。然而，多肽主链可能的构象数量如此之多，以至于随机抽样无法让蛋白质在宇宙存在的时间内折叠，这就是莱文塔尔悖论。我们在此表明，如果平均而言天然接触比非天然接触持续时间更长，也就是说，如果天然相互作用中接触断裂的解离速率常数低于非天然相互作用，那么蛋白质链就能高效且高保真地折叠。这一发现的一个重要结果是，蛋白质折叠无需指定特定途径。相反，已形成接触之间的动力学区分是折叠过程进行到天然状态的充分标准。成功的蛋白质折叠要求有成效的接触持续足够长的时间，以获得一定程度的概率，即在第一个相互作用单元解离之前其他天然接触得以形成。如果天然接触比非天然接触持续时间更长，这就能防止错误折叠，并为折叠过程提供朝向天然状态的方向性。如果平均而言所有接触持续时间相同，那么蛋白质链被认为是通过对所有可能构象进行随机搜索来折叠（即莱文塔尔悖论）。天然接触之间适度的协同性，即相邻接触附近解离速率降低，会将所需的解离速率比转变到一个现实的范围，并使折叠成为一个具有成核步骤的随机过程。在缔合过程方面无需引入动力学区分，缔合过程被建模为依赖于链段的扩散速率。
