Mg2+-driven selection of natural phosphatidic acids in primitive membranes

Biological membranes are composed of phospholipids comprising exclusively glycerol-1-phosphate or glycerol-3- phosphate. By contrast, primitive membranes would have been composed of heterogeneous mixtures of phospholipids, including non-natural analogues comprising glycerol-2-phosphate, as delivered by prebiotic synthesis. Thus, it is not clear how the selection of natural phospholipids could have come about. Here we show how differences in membrane properties, but not molecular proper- ties, could have been harnessed to drive the selection of natural phosphatidic acids (the biological precursors of all complex phos- pholipids) within primitive membranes. First, we demonstrate that at the molecular level, no prebiotic synthesis or hydrolysis path- way would have enabled the selection of natural phosphatidic acids. Second, we report that at the supramolecular level, natural phospholipids display a greater tendency to self-assemble in more packed and rigid membranes than non-natural analogues of the same chain length. Finally, taking advantage of these differences, we highlight that Mg2+, but not Ca2+, drives the selective precipi- tation of non-natural phosphatidic acids from heterogeneous mixtures obtained by prebiotic synthesis, leaving membranes propor- tionally enriched in natural phosphatidic acids. Our findings delineate a plausible pathway by which the transition towards biologi- cal membranes could have occurred under conditions compatible with prebiotic metal-driven processes, such as non-enzymatic RNA polymerization.