Folding and misfolding of the papillomavirus E6 interacting peptide E6ap.
Folding and misfolding of the papillomavirus E6 interacting peptide E6ap.
复制标题
乳头瘤病毒 E6 相互作用肽 E6ap 的折叠和错误折叠。
DOI：
10.1073/pnas.0431214100
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发表时间：
2003
影响因子：
11.1
通讯作者：
Freed,KarlF
中科院分区：
文献类型：
--
作者：
Cui,Bianxiao;Shen,Min-Yi;Freed,KarlF
用全原子朗之万动力学模拟方法研究了人乳头瘤病毒E6结合肽18个残基结合域片段E6AP的折叠途径。六个独立的折叠轨迹，总持续时间近2μS，都导致相同的自然状态，在这种状态下，E6AP在中央部分采用波动的α-螺旋结构(Ser4-Leu-13)，但具有非常灵活的N和C末端。从不同的核心配置开始的模拟将E6AP折叠动力学显示为具有中间错误折叠状态的两状态或三态文件夹。必需的亮氨酸疏水核心(Leu-9、Leu-12和Leu-13)在天然状态结构中保守，但在中间结构中缺失，这表明亮氨酸核心不仅对E6AP的结合活性是必需的，而且对天然结构的稳定性也是重要的。自由能图景揭示了分隔天然状态和错折状态的盆地之间的一道重要屏障。我们还讨论了驱动多肽进入其自然状态的各种潜在力量。
All-atom Langevin dynamics simulations have been performed to study the folding pathways of the 18-residue binding domain fragment E6ap of the human papillomavirus E6 interacting peptide. Six independent folding trajectories, with a total duration of nearly 2 μs, all lead to the same native state in which the E6ap adopts a fluctuating α-helix structure in the central portion (Ser-4–Leu-13) but with very flexible N and C termini. Simulations starting from different core configurations exhibit the E6ap folding dynamics as either a two- or three-state folder with an intermediate misfolded state. The essential leucine hydrophobic core (Leu-9, Leu-12, and Leu-13) is well conserved in the native-state structure but absent in the intermediate structure, suggesting that the leucine core is not only essential for the binding activity of E6ap but also important for the stability of the native structure. The free energy landscape reveals a significant barrier between the basins separating the native and misfolded states. We also discuss the various underlying forces that drive the peptide into its native state.