Characterizing the full distribution of polypeptoid end-to-end distances via combined simulation and experiment

Secondary and higher order structure as encoded in monomer sequence is critical to the function of proteins. Attainment of similar structural control in synthetic polymers offers the potential to access materials with unique properties driven by precisely-controlled structural ensembles, but remains largely out of reach due to a lack of understanding of how to control chain shape with polymer sequence, particularly in non-biological polymers. Sequence-controlled polypeptoids serve as a bridge between synthetic and biological polymers, and thus provide tremendous opportunity to develop design rules for programming primary sequence to modulate chain shape. This work demonstrates that polypeptoid conformational landscapes can be precisely probed via Double Electron Electron Resonance (DEER) spectroscopy and advanced molecular dynamics simulations, and moreover, that such synergistic experimental-computational studies elucidate the effects of polymer sequence and chemistry on conformational ensembles. Rather than obtaining an average end-to-end distance, this novel combined approach probes the full distribution of end-to-end distances and thus provides nuanced insights to structural changes that are often inaccessible by more traditional polymer characterization methods. Our results suggest that such a combined experimental-computational approach, leveraging the synthetic flexibility of the polypeptoid platform, can inform more general design rules for engineering sequence-specific polymers.