It remains unclear how polymer nanoparticles (NPs), with their uncontrolled monomer sequences and high structural flexibility, can mimic the function of natural antibodies that rely on precisely folded structures for protein recognition. Here, we propose, for the first time, a direct link between the antibody-like recognition capability of polymer NPs and their chain stretchability. Through extensive molecular dynamics (MD) simulations, we investigate the interactions between the EpCAM protein and a short linear random copolymer of varying stretchability, composed of N-isopropylacrylamide (NIPAm), hydrophobic N-tert-butylacrylamide (TBAm), and charged acrylic acid (AAc) monomers. Our results demonstrate that elongated copolymer chains form extensive binding interfaces with the protein, achieving fine matching of charged and hydrophobic sites that lead to a high degree of shape and chemical complementarity. In contrast, compressed copolymer chains, which undergo hydrophobic collapse, exhibit reduced structural flexibility and fewer accessible hydrophobic sites, resulting in diminished binding complementarity. This study reveals an unconventional recognition mechanism in which heterogeneous and dynamically fluctuating polymer networks may exploit their elongated linear segments to recognize proteins and stabilize the resulting binding complexes.
Xu et al. (Mon,) studied this question.