Sali A, Shakhnovich E, Karplus M
Department of Chemistry, Harvard University, Cambridge, Massachusetts 02138.
Nature. 1994 May 19;369(6477):248-51. doi: 10.1038/369248a0.
The number of all possible conformations of a polypeptide chain is too large to be sampled exhaustively. Nevertheless, protein sequences do fold into unique native states in seconds (the Levinthal paradox). To determine how the Levinthal paradox is resolved, we use a lattice Monte Carlo model in which the global minimum (native state) is known. The necessary and sufficient condition for folding in this model is that the native state be a pronounced global minimum on the potential surface. This guarantees thermodynamic stability of the native state at a temperature where the chain does not get trapped in local minima. Folding starts by a rapid collapse from a random-coil state to a random semi-compact globule. It then proceeds by a slow, rate-determining search through the semi-compact states to find a transition state from which the chain folds rapidly to the native state. The elements of the folding mechanism that lead to the resolution of the Levinthal paradox are the reduced number of conformations that need to be searched in the semi-compact globule (approximately 10(10) versus approximately 10(16) for the random coil) and the existence of many (approximately 10(3)) transition states. The results have evolutionary implications and suggest principles for the folding of real proteins.
多肽链所有可能构象的数量太多，无法逐一进行采样。然而，蛋白质序列确实能在数秒内折叠成独特的天然状态（莱文塔尔悖论）。为了确定如何解决莱文塔尔悖论，我们使用了一种晶格蒙特卡罗模型，其中全局最小值（天然状态）是已知的。该模型中折叠的充要条件是天然状态在势能面上是一个明显的全局最小值。这保证了在链不会被困在局部最小值的温度下天然状态的热力学稳定性。折叠从随机卷曲状态迅速坍缩为随机半紧密球体开始。然后，它通过缓慢的、速率决定的搜索过程遍历半紧密状态，以找到一个过渡态，从该过渡态链迅速折叠成天然状态。导致解决莱文塔尔悖论的折叠机制要素是在半紧密球体中需要搜索的构象数量减少（随机卷曲约为10¹⁶，半紧密球体约为10¹⁰）以及存在许多（约10³）过渡态。这些结果具有进化意义，并为真实蛋白质的折叠提供了原则。
