Effects of α-Linolenic Acid and Its Congeners on the Structural and Mechanical Properties of Model Membranes

Abstract Essential fatty acids, particularly the ω-3 species such as α-linolenic acid, are critical nutritional components, with their biosynthetic dysregulation implicated in neurodegenerative disorders. At the molecular scale, unsaturated fatty acids are recognized for their ability to modulate membrane physicochemical properties, primarily fluidity, but these interactions remain mechanistically complex and poorly defined. This study combines atomistic molecular dynamics simulations with depth-dependent fluorescence spectroscopy to systematically evaluate the impact of increasing acyl chain unsaturation on model lipid bilayers. By examining both protonated and deprotonated states, we demonstrate that ionization significantly dictates fatty acid localization within the bilayer, but the differences in membrane properties are relatively less pronounced. Our findings reveal that fatty acid effects are highly anisotropic, resulting in non-uniform perturbations to membrane structural and mechanical profiles. Crucially, the relationship between degree of unsaturation and membrane fluidity is nonlinear. Paradoxically, α-linolenic acid, despite possessing three double bonds, does not always induce the largest degree of membrane disorder. Instead, fatty acids with lower unsaturation, such as oleic and linoleic acids, could exhibit more pronounced increase in fluidity in a position-dependent manner. This non-monotonic behavior challenges the prevailing assumption in membrane biophysics that unsaturation correlates linearly with disorder, suggesting that existing predictive models require refinement to account for these specific molecular differences.