Molecular Origins of Catalysis in Random Heteropolymer Enzyme Mimics through All-Atom Simulations

Abstract Random heteropolymers (RHPs) have recently emerged as synthetic macromolecules capable of enzyme-inspired catalysis despite lacking defined secondary and tertiary structures. However, the molecular origins of their catalytic activity remain less understood. Here, we use all-atom molecular dynamics simulations to investigate a methacrylate-based RHP shown to experimentally catalyze the selective cyclization of citronellal. Despite its high anionic monomer content, the polymer self-assembles into molten globules with heterogeneous surfaces due to high hydrophobic content. This dynamic organization creates chemically distinct binding interfaces where substrates encounter local environments enriched in specific monomers. Anionic sulfopropyl methacrylate groups preferentially associate with protonated intermediates, providing electrostatic stabilization relevant to catalysis. Free energy calculations reveal a reduced barrier for substrate conformational closure that promotes reactive geometries in hydrophobic environments, relating to hydrophobic patches found on the RHP. We further observe selective adsorption behavior when multiple substrates are present, with isopulegol desorbing more rapidly than citronellal or menthoglycol, consistent with favorable product release and catalytic turnover. Together, these findings demonstrate that RHPs without rigid folds can create dynamic, chemically heterogeneous microenvironments shaped by monomer composition and sequence, enabling electrostatic and geometric stabilization, providing a molecular rationale for their experimentally observed catalytic function.