Most proteins fold during biosynthesis on the ribosome¹, and co-translational folding energetics, pathways and outcomes of many proteins have been found to differ considerably from those in refolding studies^{2,3,4,5,6,7,8,9,10}. The origin of this folding modulation by the ribosome has remained unknown. Here we have determined atomistic structures of the unfolded state of a model protein on and off the ribosome, which reveal that the ribosome structurally expands the unfolded nascent chain and increases its solvation, resulting in its entropic destabilization relative to the peptide chain in isolation. Quantitative ¹⁹F NMR experiments confirm that this destabilization reduces the entropic penalty of folding by up to 30 kcal mol⁻¹ and promotes formation of partially folded intermediates on the ribosome, an observation that extends to other protein domains and is obligate for some proteins to acquire their active conformation. The thermodynamic effects also contribute to the ribosome protecting the nascent chain from mutation-induced unfolding, which suggests a crucial role of the ribosome in supporting protein evolution. By correlating nascent chain structure and dynamics to their folding energetics and post-translational outcomes, our findings establish the physical basis of the distinct thermodynamics of co-translational protein folding.

大多数蛋白质在核糖体上生物合成期间折叠¹ ，并且发现许多蛋白质的共翻译折叠能量、途径和结果与重折叠研究中的结果有很大不同^{2,3,4,5,6,7,8,9, 10} .核糖体这种折叠调节的起源仍然未知。在这里，我们确定了核糖体上和核外模型蛋白质的未折叠状态的原子结构，这表明核糖体在结构上扩展了未折叠的新生链并增加了其溶剂化，导致其相对于孤立的肽链的熵不稳定。定量¹⁹ F NMR 实验证实，这种去稳定性可将折叠的熵损失降低高达 30 kcal mol ^-1并促进核糖体上部分折叠中间体的形成，这一观察结果延伸到其他蛋白质结构域，并且对于某些蛋白质来说是必须获得的他们的活性构象。热力学效应还有助于核糖体保护新生链免受突变诱导的展开，这表明核糖体在支持蛋白质进化中发挥着至关重要的作用。通过将新生链结构和动力学与其折叠能量学和翻译后结果相关联，我们的研究结果建立了共翻译蛋白质折叠的独特热力学的物理基础。