Designing single polymer chain nanoparticles to mimic biomolecular hydration frustration

Native folded proteins rely on sculpting the local chemical environment of their active or binding sites, as well as their shapes. In particular, proteins exhibit a phenomenon known as “hydration frustration”, i.e. the ability to control the dehydration of hydrophilic and the hydration of hydrophobic residues, respectively, to amplify their chemical or binding activity. Here, we uncover that single polymer chain nanoparticles formed by random heteropolymers composed of three or more components can display similar levels of hydration frustration. We categorize these nanoparticles into three types: i) fully-frustrated globules, where both types of residues display frustrated states, ii) semi-frustrated, with either hydrophobic or hydrophilic residues in a frustrated state, and iii) core-shell nonfrustrated globules. Based on our results, we propose a series of physicochemical rules that determine the state of these nanoparticles. The rules have been tested in both atomistic and simplified Monte Carlo models of single polymer chain nanoparticles with different backbones and residues to show their generality. Our work provides critical insights into the design of single chain nanoparticles, an emerging polymer modality that achieves the ease and cost of fabrication of polymeric material with the functionality of biological proteins.