Accurate Modeling of Helical Structures in Disordered Proteins at Residue Resolution: From Single Chains to Condensates

Coarse-grained models of intrinsically disordered proteins (IDPs) have been successfully used to describe protein phase behavior while treating IDPs as fully flexible chains and neglecting their ability to form secondary structures. However, structures such as transiently formed alpha-helices are known to impact IDP phase behavior. Here we add a novel potential to the Mpipi model that can capture the helical behavior of IDPs. Using a Gaussian process workflow and a bioinformatics informed approach, we parameterize our model by matching experimental and simulation data of helical peptides. We demonstrate our model’s accuracy and transferability by validating it against the residue-specific helical content of IDPs in atomistic simulations and NMR experiments, experimentally determined dissociation constants of IDPs binding structured proteins via helical binding motifs, and experimental saturation concentrations for phase-separating IDPs with known helical domains. Future work will probe how alpha-helix motifs in IDPs can alter the phase separation propensity of proteins and material properties of biomolecular condensates.