Omega fatty acids are currently being marketed as healthy food supplements as they have been implicated in multiple pathophysiological conditions, such as reducing plaque formation of A beta peptide and inhibiting SARS-CoV-2 infection. Their mode of action has been hypothesized to be via membrane reorganization by the unsaturated acyl chains, leading to the modulation of lipid-protein cross-talk. However, the lack of molecular details led us to evaluate the molecular effect of omega-6 (linolenic acid) and omega-9 (oleic acid) fatty acids on membrane organization using a consolidated approach of fluorescence spectroscopy and all-atom molecular dynamics simulation. Our results show that the effect of these omega fatty acids is sensitive to their protonation states. Contrary to the accepted notion that chain unsaturation causes membrane disordering, both experimental and simulation results demonstrate that protonated linoleic acid promotes membrane ordering, despite having two unsaturations at the fatty acyl chain. However, protonated oleic fatty acid, with reduced unsaturation, disordered the acyl chain area of the lipid membranes. Equally surprisingly, deprotonated oleic acid orders, whereas deprotonated linoleic acid disorders, the membrane core region. Interestingly, while the lipid order parameter measurements from simulations did not capture these subtle differences, the calculated rotational autocorrelation function of a membrane dye was in line with experimentally measured apparent rotational correlation times. Our work provides a comprehensive revised molecular picture of the effect of omega fatty acids on membranes and highlights the importance of rigorous comparative approaches, as experimental and simulation studies in isolation can sometimes lead to inconsistent results.

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