The use of poly(styrene-co-maleic acid) (SMA) for the solubilization of lipid membranes and membrane proteins is becoming more widespread, and with this, the need increases to better understand the chemical properties of the copolymer and how these translate into membrane solubilization properties. SMA comes in many different flavors that include the ratio of styrene to maleic acid, comonomer sequence distribution, average chain length, dispersity, and potential chemical modifications. In this work, the synthesis and membrane active properties are described for 2:1 (periodic) SMA copolymers with M_w varying from ∼1.4 to 6 kDa. The copolymers were obtained via an iterative RAFT-mediated radical polymerization. Characterization of these polymers showed that they represent a well-defined series in terms of chain length and overall composition (F_MAnh ∼ 0.33), but that there is heterogeneity in comonomer sequence distribution (F_MSS ∼ 0.50) and some dispersity in chain length (1.1 < Đ < 1.6), particularly for the larger copolymers. Investigation of the interaction of these polymers with phosphatidylcholine lipid self-assemblies showed that all copolymers inserted equally effectively into lipid monolayers, independent of the copolymer length. Nonetheless, smaller polymers were more effective at solubilizing lipid bilayers into nanodiscs, possibly because longer polymers are more prone to become intertwined with each other, thereby hampering their solubilization efficiency. Nanodisc sizes were independent of the copolymer length. However, nanodiscs formed with larger copolymers were found to undergo slower lipid exchange, indicating a higher stability. The results highlight the usefulness of having well-defined copolymers for systematic studies.

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