Abstract
Styrene-maleic acid (SMA) copolymers are powerful tools for the detergent-free solubilization of biological membranes. Yet the influence of specific lipids on SMA activity remains an open question. Here, we examined the effects of the mitochondriaspecific phospholipid cardiolipin on SMA-mediated membrane solubilization and their ability to form SMA-bound nanodiscs. To this end, we prepared a series of model membranes with cardiolipin and other test lipids with comparable surface charge and lateral packing characteristics. Using multiple independent experimental approaches, we found that cardiolipin inhibited SMA solubilization. Our results indicate that this effect was not attributable to headgroup charge effects, but rather to cardiolipininduced increase in lateral packing pressure at the interfacial region. Reduction of this lateral packing pressure using bilayer-active alcohols partially restored SMA solubilization. Our results highlight the importance of lipid geometry and packing in SMA nanodisc formation and could help guide the design of copolymers tailored to specific membranes.