Membrane proteins are difficult to produce due to their hydrophobic nature, usually resulting in poor yields of stable proteins. In the last decade, a new line of versatile detergent-free methods have emerged, increasing the production of membrane proteins. By directly putting the protein in a designed and controlled environment, it is possible to produce membrane proteins in different hydrophobic environments using novel solubilization techniques. One of these solubilization methods, using styrene maleic acid (SMA) polymers, has captivated structural biologists due to the amphipathic nature of the polymers and their ability to solubilize transmembrane proteins without any detergents. These polymers incorporate themselves into membranes and spontaneously form SMA-lipid particles (SMALPs). These polymers bring fresh air to the always challenging study of membrane proteins, which can now be effortlessly extracted within their native lipid environment. But in addition to that, the polymers can be chemically modified to add new capabilities. So how do these polymers solubilize membranes? We tried to answer this question using molecular dynamics simulations of membranes of different composition with SMA polymers. We show that these polymers insert, cross, and ultimately form pores in the membrane, the last step before nanodisc formation. The latter happened during self-assembly simulations, forming nanodiscs like those obtained in earlier experiments.
The cover image for the August 7 issue of the Biophysical Journal is an artistic rendering of the membrane solubilization process by SMA polymers and the formation of a lipid nanodisc. The image shows green and yellow SMA polymers in different stages of the membrane solubilization process. In the center, the SMA polymers surround the lipid patch pulled from the membrane. At the bottom-left, other polymers span through the lipid bilayer forming a membrane pore. In the back, the polymers can be seen lying on the membrane during the first contacts, just before they start to squeeze in between the lipid tails.
Our findings show the solubilization ability of SMA polymers and the details of the process at the molecular level. Our simulation protocol paves the way for further studies of SMALPs, exploring different conditions (pH, polymer composition, multi-component lipid membranes). This will help the design of optimized copolymers for nanodisc formation and drug delivery systems.
To see the article that inspired the cover, click here.
—Minmin Xue, Lisheng Chang, Ignacio Faustino, Wanlin Guo, Siewert-J. Marrink