Many large proteins suffer from slow or inefficient folding in vitro. It has long been known that this problem can be alleviated in vivo if proteins start folding cotranslationally. However, the molecular mechanisms underlying this improvement have not been well established. To address this question, we use an all-atom simulation-based algorithm to compute the folding properties of various large protein domains as a function of nascent chain length. We find that for certain proteins, there exists a narrow window of lengths that confers both thermodynamic stability and fast folding kinetics. Beyond these lengths, folding is drastically slowed by nonnative interactions involving C-terminal residues. Thus, cotranslational folding is predicted to be beneficial because it allows proteins to take advantage of this optimal window of lengths and thus avoid kinetic traps. Interestingly, many of these proteins' sequences contain conserved rare codons that may slow down synthesis at this optimal window, suggesting that synthesis rates may be evolutionarily tuned to optimize folding. Using kinetic modeling, we show that under certain conditions, such a slowdown indeed improves cotranslational folding efficiency by giving these nascent chains more time to fold. In contrast, other proteins are predicted not to benefit from cotranslational folding due to a lack of significant nonnative interactions, and indeed these proteins' sequences lack conserved C-terminal rare codons. Together, these results shed light on the factors that promote proper protein folding in the cell and how biomolecular self-assembly may be optimized evolutionarily.

中文翻译：

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共翻译折叠允许易错折叠的蛋白质规避深层动力学陷阱。

许多大蛋白质在体外折叠缓慢或效率低下。人们早就知道，如果蛋白质开始共翻译折叠，这个问题可以在体内得到缓解。然而，这种改进背后的分子机制尚未得到很好的确立。为了解决这个问题，我们使用基于全原子模拟的算法来计算各种大型蛋白质结构域的折叠特性，作为新生链长度的函数。我们发现，对于某些蛋白质，存在一个狭窄的长度窗口，既赋予热力学稳定性又赋予快速折叠动力学。超出这些长度，折叠会因涉及 C 末端残基的非天然相互作用而大大减慢。因此，预计共翻译折叠是有益的，因为它允许蛋白质利用这个最佳长度窗口，从而避免动力学陷阱。有趣的是，许多这些蛋白质的序列包含保守的稀有密码子，这些密码子可能会在这个最佳窗口减慢合成速度，这表明合成速率可以通过进化调整以优化折叠。使用动力学建模，我们表明，在某些条件下，这种减速确实通过给这些新生链更多的折叠时间来提高共翻译折叠效率。相反，由于缺乏显着的非天然相互作用，预计其他蛋白质不会从共翻译折叠中受益，实际上这些蛋白质的序列缺乏保守的 C 末端稀有密码子。一起，