Leveraging Shape and Interactional Anisotropy to Enhance Structural Control During Block Polymer Folding

In Nature, polypeptide chains with secondary structures precisely fold into proteins with diverse functions. Inspired by this, we apply the design rules of ordering structures to block copolymers by combining single-chain collapse with foldamer-guided ordering. The complex folding of a multiblock copolymer can be formulated as a geometrically mediated problem, where shape and connectivity provide a physical basis for entropy-driven ordering. Based on the connectivity-generalized entropic bonding theory (cEBT), we extend this framework to bonded monomers and incorporate foldamer-like directional interactions to capture local conformational preferences. We then systematically explore how monomer geometries, polymer sequences, bonding topologies, and directional interactions control the structural organization within single chains. Using molecular dynamics simulations and theory, we design a library of folding single chain nanoparticles that target previously unexplored sectors of the polymer folding space. These results establish a physical basis for programming protein-like folding in synthetic polymers.