Random heteropolymers enable non-specific protein binding and loop-mediated stabilization

Membrane proteins play essential roles in cellular signaling, transport, and catalysis, but their structural instability outside of lipid bilayers presents a major challenge for biophysical studies and therapeutic applications. Here, we demonstrate that methacrylate-based random heteropolymers (MMA-based RHPs) can stabilize the β-barrel membrane protein OmpLA in aqueous environments, without the need for lipids or detergents. Using large-scale atomistic molecular dynamics simulations, we investigate how RHP composition, binding orientation, and contact geometry affect protein stability. We find that RHPs preferentially bind to the lateral β-sheet surfaces of OmpLA while avoiding direct binding to the top and bottom loop regions. Despite this, RHPs enable contacts to the loops to loop via lateral binding due to their comparable size and spatial reach. Among various factors, loop-mediated stabilization emerges as the dominant mechanism: increased RHP contact with flexible loop regions reduces local fluctuations and correlates with enhanced global structural integrity. This effect is prominent for MMA-based RHPs, which present a chemically heterogeneous, patchy binding interface, unlike core–shell architectures formed by other backbones. Our findings reveal a non-specific yet effective way of protein stabilization driven by loop-targeting interactions, offering design principles for polymer-based chaperonin mimetics to stabilize membrane proteins in abiotic environments.