Quantifying Polypeptoid Conformational Landscapes through Integrated Experiment and Simulation

We combine experiment and simulation to develop a powerful, validated approach for characterizing the conformational landscapes of disordered polypeptoids. Polypeptoids have become an important class of polymers, capable of precisely defined sequences while remaining gram-synthesizable-properties that have driven a rapidly expanding set of applications, including antifoulants, therapeutics, sensing, and directed self-assembly. The characterization of polypeptoid structure provides critical molecular insight into sequence-structure-function relationships. Structurally disordered polypeptoids require new approaches to interrogate their wide range of conformations in solution. Here, we measure full end-to-end distance distributions, instead of configurational averages, using double electron-electron resonance DEER) spectroscopy and enhanced sampling molecular modeling. We demonstrate excellent agreement between the experiments and simulations for a set of model hydrophilic polypeptoids. Moreover, we illustrate the utility of this combined experiment-simulation approach in probing structure-function relationships by characterizing the basic polymer physics of this polypeptoid series, demonstrating that the polypeptoids probed here exhibit excluded volume behavior.