Cotranslational folding depends on the folding speed and stability of the nascent protein. It remains difficult, however, to predict which proteins cotranslationally fold. Here, we simulate evolution of model proteins to investigate how native structure influences evolution of cotranslational folding. We developed a model that connects protein folding during and after translation to cellular fitness. Model proteins evolved improved folding speed and stability, with proteins adopting one of two strategies for folding quickly. Low contact order proteins evolve to fold cotranslationally. Such proteins adopt native conformations early on during the translation process, with each subsequently translated residue establishing additional native contacts. On the other hand, high contact order proteins tend not to be stable in their native conformations until the full chain is nearly extruded. We also simulated evolution of slowly translating codons, finding that slower translation speeds at certain positions enhances cotranslational folding. Finally, we investigated real protein structures using a previously published data set that identified evolutionarily conserved rare codons in Escherichia coli genes and associated such codons with cotranslational folding intermediates. We found that protein substructures preceding conserved rare codons tend to have lower contact orders, in line with our finding that lower contact order proteins are more likely to fold cotranslationally. Our work shows how evolutionary selection pressure can cause proteins with local contact topologies to evolve cotranslational folding.

中文翻译：

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蛋白质结构对共翻译折叠进化的影响

共翻译折叠取决于新生蛋白质的折叠速度和稳定性。然而，预测哪些蛋白质共翻译折叠仍然很困难。在这里，我们模拟模型蛋白质的进化，以研究天然结构如何影响共翻译折叠的进化。我们开发了一个模型，将翻译期间和之后的蛋白质折叠与细胞健康联系起来。模型蛋白质进化出更高的折叠速度和稳定性，蛋白质采用两种快速折叠策略之一。低接触阶蛋白质进化为共翻译折叠。这些蛋白质在翻译过程的早期采用天然构象，每个随后翻译的残基建立额外的天然接触。另一方面，高接触顺序蛋白质在其天然构象中往往不稳定，直到整个链几乎被挤出。我们还模拟了缓慢翻译密码子的进化，发现某些位置较慢的翻译速度会增强共翻译折叠。最后，我们使用先前公布的数据集研究了真实的蛋白质结构，该数据集确定了大肠杆菌基因中进化上保守的稀有密码子，并将此类密码子与共翻译折叠中间体相关联。我们发现保守稀有密码子之前的蛋白质亚结构往往具有较低的接触顺序，这与我们的发现一致，即较低的接触顺序蛋白质更有可能在共翻译中折叠。我们的工作展示了进化选择压力如何导致具有局部接触拓扑结构的蛋白质进化出共翻译折叠。