Architecting megamolecule self-assembly networks: Insights from coarse-grained simulations and design strategies

This work describes the use of molecular dynamics strategies to design megamolecule building blocks for self-assembly networks. The megamolecules are engineered by attaching four Cutinase-SnapTag fusion proteins (CS fusions) to a four-armed linker, followed by functionalizing each fusion with a terpyridine linker. This functionality is designed to participate in metal-mediated self-assembly to form networks. This study presents a molecular dynamics simulation-guided approach for the design of megamolecules, aimed at streamlining the typically time-consuming and labor-intensive experimental process. We designed eleven candidate megamolecules and identified the most promising linker, (EAAAK)2, along with the optimal experimental conditions through a combination of all-atom molecular dynamics, enhanced sampling, and larger-scale coarse-grained molecular dynamics simulations. Our simulation findings were validated and found to be consistent with experimental results. Significantly, this study offers valuable insights into the extensive fabrication of megamolecule networks, and provides a novel and general strategy for large biomolecular material designs using bottom-up coarse-grained simulations for the first time.