Folding, misfolding, and amyloid protofibril formation of WW domain FBP28
Folding, misfolding, and amyloid protofibril formation of WW domain FBP28
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DOI：
10.1529/biophysj.105.076406
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发表时间：
2006-06-01
影响因子：
3.4
通讯作者：
Tam, James P.
中科院分区：
文献类型：
--
作者：
Mu, Yuguang;Nordenskiold, Lars;Tam, James P.
我们采用复制交换分子动力学计算机模拟方法，在原子分辨率下，用显式水模型研究了形成蛋白结合蛋白28（FBP 28）的三股β链WW结构域的折叠机制.扩展采样在很宽的温度范围内获得的自由能，焓，和熵的表面作为结构坐标的函数已经执行。模拟从不同的构象开始，涵盖折叠和展开状态。在自由能景观的过渡态被确定和它的结构和f-值进行了比较，从同源蛋白质，脯氨酰异构酶Pin 1 WW域的实验数据。一个稳定的中间状态被发现在模拟过程中积累，其特征在于羧基末端β-链3具有错误的氢键，并且其中结构异质性是由于非天然转II形成。此外，FBP 28 WW结构域的聚集行为可能与一种这样的错误折叠结构有关，其具有比天然二聚体低得多的二聚体形成自由能。基于错误折叠的二聚体，聚集形成原纤维结构进行了讨论。
We study the folding mechanism of a triple beta-strand WW domain from the Formin binding protein 28 (FBP28) at atomic resolution with explicit water model using replica exchange molecular dynamics computer simulations. Extended sampling over a wide range of temperatures to obtain the free energy, enthalpy, and entropy surfaces as a function of structural coordinates has been performed. Simulations were started from different con. gurations covering the folded and unfolded states. In the free energy landscape a transition state is identified and its structures and f-values are compared with experimental data from a homologous protein, the prolyl-isomerase Pin1 WW domain. A stable intermediate state is found to accumulate during the simulation characterized by the carboxyl-terminal beta-strand 3 having misregistered hydrogen bonds and where the structural heterogeneity is due to nonnative turn II formation. Furthermore, the aggregation behavior of the FBP28 WW domain may be related to one such misfolded structure, which has a much lower free energy of dimer formation than that of the native dimer. Based on the misfolded dimer, aggregation to form protofibril structure is discussed.