Biomolecular condensates, which are typically thought to form via phase separation driven by disordered protein domains, concentrate a variety of disordered and structured biomolecular components. Here, we ask whether the unique physicochemical environment of condensates can manipulate the folding landscape of simple protein structures-namely, the protein alpha-helix. To this end, we have developed and validated a reside-resolution coarse-grained model to describe protein alpha-helices. Using this model, we probe how model condensates formed of short scaffold peptides influence the folding thermodynamics and kinetics of individual alpha-helices. We extend the model to probe the behavior of disordered proteins, such as the TDP43, Annexin A11, and androgen receptor protein low complexity domains, within condensates formed of long disordered peptides. Our findings indicate that condensates which concentrate a high number of residues that participate in strong multivalent interactions, for example, aromatic and charged residues, counteract to varying degrees the crowding effect of a dense environment and favor a coil state within these helical motifs. Further, these domains experience a high degree of kinetic frustration with folding transition times that differ among condensates of distinct compositions. These results serve as a foundation for understanding the biophysical implications of condensates on folded protein domains and the role of these helical motifs in condensate associated protein aggregation diseases.
Hess et al. (Sun,) studied this question.