Quantifying Polypeptoid Conformational Landscapes through Integrated Experiment and Simulation
Sally Jiao, Audra J. DeStefano, Jacob I. Monroe, Mikayla Barry, Nicholas Sherck, Thomas M. Casey, Rachel A. Segalman, Songi Han, M. Scott Shell
Abstract
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.