Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
PLoS Comput Biol. 2011 Oct;7(10):e1002169. doi: 10.1371/journal.pcbi.1002169. Epub 2011 Oct 13.
Identifying the forces that drive proteins to misfold and aggregate, rather than to fold into their functional states, is fundamental to our understanding of living systems and to our ability to combat protein deposition disorders such as Alzheimer's disease and the spongiform encephalopathies. We report here the finding that the balance between hydrophobic and hydrogen bonding interactions is different for proteins in the processes of folding to their native states and misfolding to the alternative amyloid structures. We find that the minima of the protein free energy landscape for folding and misfolding tend to be respectively dominated by hydrophobic and by hydrogen bonding interactions. These results characterise the nature of the interactions that determine the competition between folding and misfolding of proteins by revealing that the stability of native proteins is primarily determined by hydrophobic interactions between side-chains, while the stability of amyloid fibrils depends more on backbone intermolecular hydrogen bonding interactions.
确定导致蛋白质错误折叠和聚集的力，而不是折叠成其功能状态，对于我们理解生命系统以及我们对抗蛋白质沉积紊乱（如阿尔茨海默病和海绵状脑病）的能力至关重要。我们在这里报告了一个发现，即在蛋白质折叠到其天然状态和错误折叠到替代淀粉样结构的过程中，疏水相互作用和氢键相互作用之间的平衡是不同的。我们发现，折叠和错误折叠的蛋白质自由能景观的最小值分别倾向于由疏水相互作用和氢键相互作用主导。这些结果描述了决定蛋白质折叠和错误折叠竞争的相互作用的本质，通过揭示天然蛋白质的稳定性主要取决于侧链之间的疏水相互作用，而淀粉样纤维的稳定性更多地取决于骨架分子间氢键相互作用。
