Molecular dynamics as a tool for unveiling protein-like folding behavior in urethane-based macromolecules: the effect of chain length on the secondary structure of oligourethanes

Abstract

Sequence-defined and stereocontrolled polymers represent an emerging class of macromolecules, offering the potential to design protein-like molecular architectures based on abiotic polymer backbones. These systems hold promise for applications requiring specific intermolecular interactions, which can be exploited, for instance, in catalysis or sensing. Realizing this potential necessitates a deeper understanding of their folding behavior beyond aqueous solutions, which resemble physiological conditions. In this study, the influence of chain length on the folding of model oligourethanes – comprising four, eight, and twelve monomer building blocks, is investigated in silico by molecular dynamics (MD) and experimentally using circular dichroism spectroscopy (CD). It is demonstrated that stabilizing interactions constrain the expansion of their conformational space while also revealing the inherent limitations of such processes. The increase of chain length from four to eight units results in the stabilization of the helical secondary structure. Further elongation leads to the formation of more complex structures, which appear as a combination of looping helix motifs, resembling tertiary structures. Importantly, to learn about the structural details of studied systems, a set of methodological adaptations is proposed to enhance the applicability of conventional data analysis techniques, which are typically applied to amide-based macromolecules, to study secondary structure of urethane-based sequence-defined systems.