Energy Landscape and Stability in Random Heteropolymers: Somewhere Between Protein Folding and Plastic Miscibility

Synthetic random heteropolymers (RHPs) offer a versatile platform for mimicking protein-like functions through their sequence and structure ensembles, providing a cost-effective and scalable alternative to natural proteins. Unlike the well-studied energy landscapes of protein folding, the energy landscape of RHP folding, or more generally, collapse, remains largely unexplored. Here, we investigate the energy landscape and structural stability of a recently emergent class of methyl methacrylate-based RHPs. By conducting microsecond-scale atomistic molecular dynamics simulations with umbrella sampling, we propose a hierarchically rugged free energy landscape characterized by high energy barriers separating broad minima with internally rugged basins that permit local structural fluctuations. Identical local sequences are found to be able to adopt diverse conformations. Using XGBoost and SHAP analysis, we identify key contact patterns critical for structural stability. These include specific residue–residue contacts reminiscent of those observed in protein folding, and position-nonspecific interactions, such as contacts between backbone and polar or hydrophobic side groups, which are related to monomer miscibility. This latter relationship resembles the design rules in plastics. Moreover, the inherent diversity of microenvironments in RHPs highlights their potential to incorporate functional ligands, enabling versatile applications such as catalysis. This work elucidates both the similarities and differences among RHPs, proteins, and plastics, providing fundamental insight into the collapse free energy landscape, structural stability, and functional adaptability of RHPs.