Charge Drives Initiation and Regulation of Blood Coagulation Cascade: Ions and Proteins

Abstract

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 to 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 competes with Ca2+ in binding PS lipids, leading to a negative impact on key steps in the blood coagulation cascade. While many experimental studies have been performed on lactadherin's C2 domain (LactC2) binding affinity for PS molecules, there are no previous atomistic computational studies characterizing LactC2 interactions with PS lipids in the plasma membrane. We performed extensive sampling of LactC2-membrane interactions in the presence and absence of Ca2+. We aim to characterize PS-Ca2+ and PS-LactC2 interactions and to understand how they initiate and impede blood coagulation, respectively. We observe long-lived PS-Ca2+ and PS-LactC2 interactions in all membrane systems. However, the protein side-chains involved in PS-LactC2 interactions appear to be affected by the presence of Ca2+. Simulations captured spontaneous insertion of LactC2 into the lipid bilayer and conformational changes of the plasma membrane in the presence of Ca2+. Characterizing the competing interactions between Ca2+ and lactadherin with PS lipids can lead to a greater understanding of the activation and regulation of the blood coagulation cascade and the many related health issues associated with coagulopathy and thrombophilia.