Centro de Física da Matéria Condensada and Departamento de Física, Universidade de Lisboa, Av. Prof. Gama Pinto 2, 1649-003 Lisboa, Portugal.
J Chem Phys. 2013 Jun 7;138(21):215101. doi: 10.1063/1.4808044.
We performed extensive lattice Monte Carlo simulations of ribosome-bound stalled nascent chains (RNCs) to explore the relative roles of native topology and non-native interactions in co-translational folding of small proteins. We found that the formation of a substantial part of the native structure generally occurs towards the end of protein synthesis. However, multi-domain structures, which are rich in local interactions, are able to develop gradually during chain elongation, while those with proximate chain termini require full protein synthesis to fold. A detailed assessment of the conformational ensembles populated by RNCs with different lengths reveals that the directionality of protein synthesis has a fine-tuning effect on the probability to populate low-energy conformations. In particular, if the participation of non-native interactions in folding energetics is mild, the formation of native-like conformations is majorly determined by the properties of the contact map around the tethering terminus. Likewise, a pair of RNCs differing by only 1-2 residues can populate structurally well-resolved low energy conformations with significantly different probabilities. An interesting structural feature of these low-energy conformations is that, irrespective of native structure, their non-native interactions are always long-ranged and marginally stabilizing. A comparison between the conformational spectra of RNCs and chain fragments folding freely in the bulk reveals drastic changes amongst the two set-ups depending on the native structure. Furthermore, they also show that the ribosome may enhance (up to 20%) the population of low energy conformations for chains folding to native structures dominated by local interactions. In contrast, a RNC folding to a non-local topology is forced to remain largely unstructured but can attain low energy conformations in bulk.
我们进行了广泛的晶格蒙特卡罗模拟核糖体结合的停滞新生链 (RNC)，以探索天然拓扑和非天然相互作用在小蛋白质共翻译折叠中的相对作用。我们发现大部分天然结构的形成通常发生在蛋白质合成的后期。然而，富含局部相互作用的多结构域结构能够在链延伸过程中逐渐发展，而那些具有邻近链末端的结构则需要完整的蛋白质合成才能折叠。对具有不同长度的 RNC 所占据的构象集合进行详细评估表明，蛋白质合成的方向性对占据低能构象的概率具有微调作用。特别是，如果非天然相互作用在折叠能学中的参与程度较轻，那么形成类似天然的构象主要取决于连接末端周围接触图的性质。同样，如果 RNC 仅相差 1-2 个残基，它们就可以以显著不同的概率占据结构上分辨率良好的低能构象。这些低能构象的一个有趣的结构特征是，无论天然结构如何，它们的非天然相互作用总是长程的和略有稳定的。将 RNC 的构象谱与在本体中自由折叠的链片段进行比较，发现两种设置之间存在很大差异，具体取决于天然结构。此外，它们还表明核糖体可以提高（高达 20%）天然结构主导的局部相互作用的折叠到天然结构的低能构象的丰度。相比之下，折叠到非局部拓扑的 RNC 被迫保持大部分无结构状态，但可以在本体中获得低能构象。
