Random Heteropolymers Enable Nonspecific 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 the 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 nonspecific 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.