Anomalous behavior of membrane fluidity caused by copper-copper bond coupled phospholipids

Membrane fluidity, essential for cell functions, is obviously affected by copper, but the molecular mechanism is poorly understood. Here, we unexpectedly observed that a decrease in phospholipid (PL) bilayer fluidity caused by Cu(2+) was more significant than those by Zn(2+) and Ca(2+), while a comparable reduction occurred in the last two ions. This finding disagrees with the placement in the periodic table of Cu just next to Zn and far from Ca. The physical nature was revealed to be an anomalous attraction between Cu(+) cations, as well as the induced motif of two phospholipids coupled by Cu-Cu bond (PL-diCu-PL). Namely, upon Cu(2+) ion binding to a negatively charged phosphate group of lipid, Cu(2+) was reduced to Cu(+). The attraction of the cations then caused one Cu(+) ion simultaneously binding to two lipids and another Cu(+), resulting in the formation of PL-diCu-PL structure. In contrast, this attraction cannot occur in the cases of Zn and Ca ions. Remarkably, besides lipids, the phosphate group also widely exists in other biological molecules, including DNA, RNA, ADP and ATP. Our findings thus provide a new view for understanding the biological functions of copper and the mechanism underlying copper-related diseases, as well as lipid assembly.