Uncovering the folding mechanism of pertactin: A comparative study of isolated and vectorial folding
Uncovering the folding mechanism of pertactin: A comparative study of isolated and vectorial folding
复制标题
揭示百日咳毒素的折叠机制：分离折叠和矢量折叠的比较研究
DOI：
10.1016/j.bpj.2023.03.021
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发表时间：
2023
影响因子：
3.4
通讯作者：
Gumbart, James C.
中科院分区：
文献类型：
--
作者：
Pang, Yui Tik;Hazel, Anthony J.;Gumbart, James C.
自身转运蛋白是革兰氏阴性菌中发现的一个大家族的毒力因子，在革兰氏阴性菌的致病过程中发挥重要作用。自身转运蛋白的乘客结构域几乎总是由一个大的β-螺旋组成，其中只有一小部分与其毒力功能相关。这导致了β-螺旋结构的折叠有助于乘客结构域分泌穿过革兰氏阴性外膜的假设。在这项研究中，我们使用分子动力学模拟和增强的采样方法来调查乘客结构域的稳定性和折叠的perceptin，从百日咳博德特氏菌的自转运蛋白。具体来说，我们采用转向分子动力学来模拟整个乘客结构域的展开，以及自学习自适应伞式采样来比较β螺旋折叠横档独立（“孤立折叠”）与折叠横档顶部的能量学先前折叠的横档（“矢量折叠”）。我们的研究结果表明，与孤立折叠相比，矢量折叠是非常有利的;此外，我们的模拟表明，β-螺旋的C-末端横档对解折叠的抵抗力最强，这与先前的研究一致，该研究发现乘客结构域的C-末端一半比N-末端更稳定。总的来说，这项研究提供了新的见解的折叠过程中的一个自动转运乘客域及其在跨外膜分泌的潜在作用。
Autotransporters are a large family of virulence factors found in Gram-negative bacteria that play important roles in their pathogenesis. The passenger domain of autotransporters is almost always composed of a large β-helix, with only a small portion of it being relevant to its virulence function. This has led to the hypothesis that the folding of the β-helical structure aids the secretion of the passenger domain across the Gram-negative outer membrane. In this study, we used molecular dynamics simulations and enhanced sampling methods to investigate the stability and folding of the passenger domain of pertactin, an autotransporter fromBordetella pertussis. Specifically, we employed steered molecular dynamics to simulate the unfolding of the entire passenger domain as well as self-learning adaptive umbrella sampling to compare the energetics of folding rungs of the β-helix independently ("isolated folding") versus folding rungs on top of a previously folded rung ("vectorial folding"). Our results showed that vectorial folding is highly favorable compared with isolated folding; moreover, our simulations showed that the C-terminal rung of the β-helix is the most resistant to unfolding, in agreement with previous studies that found the C-terminal half of the passenger domain to be more stable than the N-terminal one. Overall, this study provides new insights into the folding process of an autotransporter passenger domain and its potential role in secretion across the outer membrane.