A model study of protein nascent chain and cotranslational folding using hydrophobic-polar residues.
A model study of protein nascent chain and cotranslational folding using hydrophobic-polar residues.
复制标题
使用疏水极性残基的蛋白质新生链和共翻译折叠的模型研究。
作者：
Lu,Hsiao-Mei;Liang,Jie
为了研究蛋白质初生链在生物合成过程中的折叠行为，我们使用二维正方形格子模型和优化的三维四态离散非格子模型研究了疏水和极性链模型在生长过程中的折叠行为。在分别在二维和三维空间中列举了长度为N=18和n=15的HP杂聚体的所有可能的序列和构象后，我们检查了随着新生链的增长，所采用的结构、稳定性和对单点突变的耐受性的变化。在这两个模型中，我们发现稳定的模型蛋白在生长过程中折叠的新生链数较少，而且通常只会在达到全长后才折叠。在少数情况下，稳定蛋白质的部分链折叠，平均而言，这些部分构象与最终全长构象的相应部分非常相似。相反，我们发现稳定的萌发链较少的序列和类天然折叠的萌发链的序列更稳定。此外，这些稳定的序列通常可以有更多的点突变，并且仍然折叠成与野生型序列相同的构象。我们的结果表明，稳定的蛋白质在生物合成过程中不太可能被困在亚稳态构象中，并且对点突变更具抵抗力。我们的结果还表明，在新生的链折叠过程中，不太稳定的蛋白质将需要伴侣和其他因素的帮助。结合其他报道的研究，似乎共翻译折叠可能不是小蛋白活体蛋白折叠的一般机制，而在体外折叠研究中，仍然与理解蛋白质如何在生物学上折叠有关。蛋白质2008。©2007 Wiley-Liss Inc.
To study protein nascent chain folding during biosynthesis, we investigate the folding behavior of models of hydrophobic and polar (HP) chains at growing length using both two‐dimensional square lattice model and an optimized three‐dimensional 4‐state discrete off‐lattice model. After enumerating all possible sequences and conformations of HP heteropolymers up to lengthN= 18 andN= 15 in two and three‐dimensional space, respectively, we examine changes in adopted structure, stability, and tolerance to single point mutation as the nascent chain grows. In both models, we find that stable model proteins have fewer folded nascent chains during growth, and often will only fold after reaching full length. For the few occasions where partial chains of stable proteins fold, these partial conformations on average are very similar to the corresponding parts of the final conformations at full length. Conversely, we find that sequences with fewer stable nascent chains and sequences with native‐like folded nascent chains are more stable. In addition, these stable sequences in general can have many more point mutations and still fold into the same conformation as the wild type sequence. Our results suggest that stable proteins are less likely to be trapped in metastable conformations during biosynthesis, and are more resistant to point‐mutations. Our results also imply that less stable proteins will require the assistance of chaperone and other factors during nascent chain folding. Taken together with other reported studies, it seems that cotranslational folding may not be a general mechanism ofin vivoprotein folding for small proteins, andin vitrofolding studies are still relevant for understanding how proteins fold biologically. Proteins 2008. © 2007 Wiley‐Liss, Inc.