Abstract

During the final step of the bacteriophage infection cycle, the cytoplasmic membrane of host cells is disrupted by small membrane proteins called holins. The function of holins in cell lysis is carried out by forming a highly ordered structure called lethal lesion, in which the accumulation of holins in the cytoplasmic membrane leads to the sudden opening of a hole in the middle of this oligomer. Previous studies showed that dimerization of holins is a necessary step to induce their higher order assembly. However, the molecular mechanism underlying the holin-mediated lesion formation is not well understood. In order to elucidate the functions of holin, we first computationally constructed a structural model for our testing system: the holin S105 from bacteriophage lambda. All atom molecular dynamic simulations were further applied to refine its structure and study its dynamics as well as interaction in lipid bilayer. Additional simulations on association between two holins provide supportive evidence to the argument that the C-terminal region of holin plays a critical role in regulating the dimerization. In detail, we found that the adhesion of specific nonpolar residues in transmembrane domain 3 (TMD3) in a polar environment serves as the driven force of dimerization. Our study therefore brings insights to the design of binding interfaces between holins, which can be potentially used to modulate the dynamics of lesion formation.

Graphic Abstract

中文翻译：

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膜双层中Holin S105的计算模拟及其通过Helix-Turn-Helix Motif的二聚化

摘要

在噬菌体感染周期的最后一步，宿主细胞的细胞质膜被称为 holins 的小膜蛋白破坏。holins 在细胞裂解中的功能是通过形成一种称为致死病变的高度有序结构来实现的，其中 holins 在细胞质膜中的积累导致该寡聚​​体中间突然打开一个孔。先前的研究表明，holins 的二聚化是诱导其高阶组装的必要步骤。然而，洞介导的病变形成的分子机制尚不清楚。为了阐明 holin 的功能，我们首先为我们的测试系统计算构建了一个结构模型：来自 λ 噬菌体的 holin S105。进一步应用所有原子分子动力学模拟来改进其结构并研究其动力学以及脂质双层中的相互作用。对两个 holin 之间关联的额外模拟为 holin 的 C 末端区域在调节二聚化中起关键作用的论点提供了支持性证据。详细地，我们发现在极性环境中跨膜结构域 3 (TMD3) 中特定非极性残基的粘附是二聚化的驱动力。因此，我们的研究为 holins 之间的结合界面设计带来了见解，这可能用于调节病变形成的动力学。对两个 holin 之间关联的额外模拟为 holin 的 C 末端区域在调节二聚化中起关键作用的论点提供了支持性证据。详细地，我们发现在极性环境中跨膜结构域 3 (TMD3) 中特定非极性残基的粘附是二聚化的驱动力。因此，我们的研究为 holins 之间的结合界面设计带来了见解，这可能用于调节病变形成的动力学。对两个 holin 之间关联的额外模拟为 holin 的 C 末端区域在调节二聚化中起关键作用的论点提供了支持性证据。详细地，我们发现在极性环境中跨膜结构域 3 (TMD3) 中特定非极性残基的粘附是二聚化的驱动力。因此，我们的研究为 holins 之间的结合界面设计带来了见解，这可能用于调节病变形成的动力学。

图形摘要