Charged molecular species, such as ions, play a vital role in the life of the cell. In particular, divalent calcium ions (Ca2+) are critical for activating cellular membranes. Interactions between Ca2+ and anionic phosphatidylserine (PS) lipids result in structural changes of the plasma membrane and are vital for many signaling pathways, such as the tightly regulated blood coagulation cascade. Upon cell damage, PS lipids are externalized to the outer leaflet, where they are not only exposed to Ca2+, but also to proteins. Lactadherin is a glycoprotein, important for cell adhesion, that can act as an anticoagulant. While a number of experimental studies have been performed on lactadherin's C2 domain's (LactC2) binding affinity for PS molecules, an atomistic description of LactC2 interactions with PS lipids in the plasma membrane is lacking. We performed extensive all-atom molecular dynamics simulations of mixed lipid bilayers and experimental characterization of LactC2-membrane interactions in the presence and absence of Ca2+ and characterized PS-Ca2+ and PS-LactC2 interactions to guide our understanding of how these interactions initiate and impede blood coagulation, respectively. The captured spontaneously formed long-lived PS-Ca2+ and PS-LactC2 complexes revealed that the protein side chains involved in PS-LactC2 interactions appear to be affected by the presence of Ca2+. The degree of LactC2 insertion into the lipid bilayer also appears to be dependent on the presence of Ca2+. Characterizing the interactions between Ca2+ and LactC2 with PS lipids can lead to a greater understanding of the activation and regulation of the blood coagulation cascade and of the basis ofcharged species interactions with the lipid membrane.

中文翻译：

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蛋白质和离子竞争膜相互作用：乳酸粘附素的情况

带电的分子物种（例如离子）在细胞生命中起着至关重要的作用。特别是，二价钙离子（Ca2 +）对于激活细胞膜至关重要。Ca2 +和阴离子磷脂酰丝氨酸（PS）脂质之间的相互作用导致质膜的结构变化，并且对于许多信号传导途径（例如严格调节的凝血级联）至关重要。一旦细胞受损，PS脂质就被外部小叶外在化，在那里它们不仅暴露于Ca2 +，而且也暴露于蛋白质。Lactadherin是一种糖蛋白，对细胞粘附很重要，可以充当抗凝剂。尽管已经对乳黏附素的C2结构域（LactC2）对PS分子的结合亲和力进行了许多实验研究，但缺乏LactC2与质膜中PS脂质相互作用的原子描述。我们进行了混合脂质双层的全原子分子动力学模拟，并在存在和不存在Ca2 +的情况下对LactC2-膜相互作用进行了实验表征，并表征了PS-Ca2 +和PS-LactC2相互作用，以指导我们对这些相互作用如何引发和阻碍血液的理解分别凝结。捕获的自发形成的长寿命PS-Ca2 +和PS-LactC2复合物表明，参与PS-LactC2相互作用的蛋白质侧链似乎受Ca2 +的存在影响。LactC2插入脂质双层的程度也似乎取决于Ca2 +的存在。