Alpha-Crystallin-Membrane Association Modulated by Phospholipid Acyl Chain Length and Degree of Unsaturation

α-crystallin-membrane association increases with age and cataracts, with the primary association site of α-crystallin being phospholipids. However, it is unclear if phospholipids’ acyl chain length and degree of unsaturation influence α-crystallin association. We used the electron paramagnetic resonance approach to investigate the association of α-crystallin with phosphatidylcholine (PC) membranes of different acyl chain lengths and degrees of unsaturation and with and without cholesterol (Chol). The association constant (K_a) of α-crystallin follows the trends, i.e., K_a (14:0–14:0 PC) > K_a (18:0–18:1 PC) > K_a (18:1–18:1 PC) ≈ K_a (16:0–20:4 PC) where the presence of Chol decreases K_a for all membranes. With an increase in α-crystallin concentration, the saturated and monounsaturated membranes rapidly become more immobilized near the headgroup regions than the polyunsaturated membranes. Our results directly correlate the mobility and order near the headgroup regions of the membrane with the K_a, with the less mobile and more ordered membrane having substantially higher K_a. Furthermore, our results show that the hydrophobicity near the headgroup regions of the membrane increases with the α-crystallin association, indicating that the α-crystallin-membrane association forms the hydrophobic barrier to the transport of polar and ionic molecules, supporting the barrier hypothesis in cataract development.