Multiscale Molecular Dynamics Studies Reveal Different Modes of Receptor Clustering by Gb3-Binding Lectins
Multiscale Molecular Dynamics Studies Reveal Different Modes of Receptor Clustering by Gb3-Binding Lectins
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DOI：
10.1021/acs.jctc.0c01145
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发表时间：
2021-04-01
影响因子：
5.5
通讯作者：
Roemer, Winfried
中科院分区：
文献类型：
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作者：
Kociurzynski, Raisa;Makshakova, Olga N.;Roemer, Winfried
病原凝集素识别宿主细胞膜上的碳水化合物受体是微生物入侵的关键步骤。两种细菌凝集素，即来自志贺菌的滋贺毒素B亚基（StxB）和来自铜绿假单胞菌的凝集素I（LecA），对相同的半乳糖脂-神经酰胺三己糖（Gb 3）具有特异性。在这项研究中，我们提出了一个粗粒（CG）模型的Gb 3，我们进一步应用到解开糖脂结合的分子细节的DOPC/胆固醇/Gb 3双层的表面上的两个凝集素。在时间尺度为几十微秒的cg分子动力学模拟中，Gb 3是随机分布的。StxB或LecA两者的结合伴随着胆固醇环境中的Gb 3聚集，并且在蛋白质附近排除DOPC。StxB被所有15个结合位点结合诱导膜弯曲，而LecA在大部分时间内与四个结合位点中的两个相互作用，导致模型膜的向内曲率较小。稳定的相互作用发生时，LecA是正常的膜表面。此外，全原子模拟显示，LecA绑定Gb 3的头基在两个可能的构象的碳水化合物部分在无蛋白质的条件下观察到的只有一个。结果揭示了两种凝集素与膜表面Gb 3之间相互作用的机制，并为在大时空尺度上研究更复杂的系统提供了粗粒度模型。
The recognition of carbohydrate receptors on host cell membranes by pathogenic lectins is a crucial step in the microbial invasion. Two bacterial lectins, the B-subunit of Shiga toxin from Shigella dysenteria (StxB) and lectin I from Pseudomonas aeruginosa (LecA), are specific to the same galactolipid-globotriaosylceramide (Gb3). In this study we present a coarse-grained (cg) model of Gb3, which we further apply to unravel the molecular details of glycolipid binding by two lectins on the surface of a DOPC/cholesterol/Gb3 bilayer. In cg molecular dynamics simulations with time scales of dozens of microseconds, Gb3 was randomly distributed. The binding of both StxB or LecA is accompanied by Gb3 clustering in a cholesterol environment and with exclusion of DOPC in protein vicinity. StxB being bound by all 15 binding sites induced membrane bending, while LecA interacted with two out of four binding sites for most of the time causing a smaller inward curvature of the model membrane. Stable interactions occurred preferably when LecA was normal to the membrane surface. Furthermore, all-atom simulations revealed that LecA bound Gb3's headgroup at only one out of two possible conformations of the carbohydrate moiety observed at protein-free conditions. The results shed light on the mechanism of interactions between two lectins and Gb3 on the membrane surface and offer a coarse-grained model to study more complex systems at large spatiotemporal scales.