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

Biological membranes are composed exclusively of phospholipids comprising glycerol-1-phosphate or glycerol-3-phosphate. By contrast, primitive membranes would have likely 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 supramolecular properties, but not molecular properties, could have driven the selection of natural phosphatidic acids in primitive membranes. First, we demonstrate that at the molecular level it is unlikely that any prebiotic synthesis or hydrolysis pathway 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 Na⁺, K⁺, Ca²⁺ or Zn²⁺, drives the selective precipitation of non-natural phosphatidic acids from heterogeneous mixtures obtained by prebiotic synthesis, leaving membranes proportionally enriched in natural phosphatidic acids. Our findings delineate a plausible pathway by which the transition towards biological membranes could have occurred under conditions compatible with prebiotic metal-driven processes, such as non-enzymatic RNA polymerization.