From sequence definition to structure-property relationships in discrete synthetic macromolecules: insights from molecular modeling

Abstract

Inspired by the exquisite properties emerging from the sequence order in nucleic acids and proteins, researchers are increasingly considering synthetic sequence-defined macromolecules (SDMs) to reach precise functions, e.g. for catalysis, data storage, energy, and health. While researchers develop iterative techniques permitting the synthesis of perfectly defined sequences, there is still an important gap to achieve the desired properties leading to their utilization as materials. This arises from the fact that the effect of the sequence order on the 3D structure is unknown for most synthetic SDMs. While the Protein Data Bank gathers hundreds of thousands of elucidated 3D structures, and many more computed (using e.g. AlphaFold), extended information on sequence-structure relationships do not exist yet for synthetic SDMs. To tackle this problem for relatively flexible macromolecules, one can nowadays utilize the existing tools of molecular modeling. In this Review, we report advanced practices to reveal the 3D structures and the interactions, through the combination of molecular dynamics simulations and network analysis applied to different SDMs. By combining the computational results to the experimental ones, we show the potential of this approach for understanding sequence-structure-property relationships in discrete macromolecular systems, towards guiding their rational design for specific functions.