Phosphatidic acid is the simplest (diacyl)glycerophospholipid present in cells and is now a well established second messenger with direct biological functions. It is specifically recognized by diverse proteins and plays an important role in cellular signaling and membrane dynamics in all eukaryotes. An important determinant of the biological functions of phosphatidic acid is its anionic headgroup. In this review we will focus on the peculiar ionization properties of phosphatidic acid and their crucial role in lipid-protein interactions. We will take a molecular approach focusing entirely on the physical chemistry of the lipid and develop a model explaining the ionization properties of phosphatidic acid, termed the electrostatic-hydrogen bond switch model. Diverse examples from recent literature in support of this model will be presented and the broader implications of our findings will be discussed.
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