Huard Fabien P E, Deane Charlotte M, Wood Graham R
Department of Statistics, Macquarie University, NSW 2109, Australia.
Bioinformatics. 2006 Jul 15;22(14):e203-10. doi: 10.1093/bioinformatics/btl248.
This study presents a novel investigation of the effect of kinetic control on cotranslational protein folding. We demonstrate the effect using simple HP lattice models and show that the cotranslational folding of proteins under kinetic control has a significant impact on the final conformation. Differences arise if nature is not capable of pushing a partially folded protein back over a large energy barrier. For this reason we argue that such constraints should be incorporated into structure prediction techniques. We introduce a finite surmountable energy barrier which allows partially formed chains to partly unfold, and permits us to enumerate exhaustively all energy pathways.
We compare the ground states obtained sequentially with the global ground states of designing sequences (those with a unique global ground state). We find that the sequential ground states become less numerous and more compact as the surmountable energy barrier increases. We also introduce a probabilistic model to describe the distribution of final folds and allow partial settling to the Boltzmann distribution of states at each stage. As a result, conformations with the highest probability of final occurrence are not necessarily the ones of lowest energy.
Software available on request.
本研究对动力学控制对共翻译蛋白质折叠的影响进行了新颖的调查。我们使用简单的HP晶格模型证明了这种影响，并表明在动力学控制下蛋白质的共翻译折叠对最终构象有重大影响。如果自然无法将部分折叠的蛋白质推过一个大的能量屏障，就会出现差异。因此，我们认为这种限制应纳入结构预测技术中。我们引入了一个有限的可克服能量屏障，它允许部分形成的链部分展开，并使我们能够详尽地列举所有能量路径。
我们将顺序获得的基态与设计序列（具有唯一全局基态的序列）的全局基态进行比较。我们发现，随着可克服能量屏障的增加，顺序基态的数量减少且变得更加紧凑。我们还引入了一个概率模型来描述最终折叠的分布，并允许在每个阶段部分达到状态的玻尔兹曼分布。结果，最终出现概率最高的构象不一定是能量最低的构象。
可根据要求提供软件。
