Molecular dynamics simulations in explicit water were carried out for two stacks, each composed of six 10-strand antiparallel β-sheets for two peptides corresponding to the diverging turn of two homologous Abl-SH3 domains. The first system, referred to as 10×6×MK contained the DLSFMKGE sequence from the Drosophila, while the second one, referred to as 10×6×KK, contained the human DLSFKKGE sequence. It was found that the 10×6×MK β-sheet stack is stable, but the 10×6×KK β-sheet stack is not. The stability of the 10×6×MK β-sheet stack results from the hydrophobic interactions of the methionine and phenylalanine residues and the leucine residues of the neighboring sheets. The Met, Phe, and Leu hydrophobic units make a hydrophobic core for the stack of β-sheets. During the MD run, the Met, Phe, and Leu residues of the neighboring β-sheets acted as a conformational switch moving the β-sheets so that the Phe residue interacted with the Met residue from the neighboring β-sheet. Replacement of Met by Lys destroys the hydrophobic core, which is the stability factor of the β-sheet stack. For the 10×6×KK system, individual β-sheets were preserved during simulations, but the interactions between the β-sheets were lost. The calculations of a six β-sheet stack confirm the conclusion drawn from our earlier studies of single β-sheet systems that the β-sheets must form stacks to be stabilized. These results suggest that the two conserved basic residues at the diverging turn of SH3 domains could act as gatekeepers to avoid aggregation.

译文

在显式水中对两个堆栈进行了分子动力学模拟,每个堆栈由两个肽的六个10链反平行 β-折叠组成,对应于两个同源Abl-SH3域的发散转向。第一个系统 (称为10 × 6 × mk) 包含果蝇的DLSFMKGE序列,而第二个系统 (称为10 × 6 × kk) 包含人类DLSFKKGE序列。发现10 × 6 × mk β-折叠堆叠是稳定的,而10 × 6 × kk β-折叠堆叠则不稳定。10 × 6 × mk β-薄片堆叠的稳定性是由蛋氨酸和苯丙氨酸残基与相邻薄片的亮氨酸残基的疏水相互作用引起的。Met,Phe和Leu疏水单元为 β-折叠堆叠形成疏水核心。在MD运行期间,相邻 β-sheet的Met,Phe和Leu残基充当构象开关,移动 β-sheet,以使Phe残基与相邻 β-sheet的Met残基相互作用。用Lys代替Met会破坏疏水核,这是 β-折叠堆叠的稳定性因子。对于10 × 6 × kk系统,在模拟过程中保留了单个 β-折叠,但是 β-折叠之间的相互作用丢失了。六个 β-sheet堆栈的计算证实了我们先前对单个 β-sheet系统的研究得出的结论,即 β-sheet必须形成堆栈才能稳定。这些结果表明,在SH3结构域发散的转弯处的两个保守的碱性残基可以充当网守以避免聚集。

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