Functional specificity of biomolecular interactions has been traditionally associated with ordered molecular structures. However, consistent with recent advances in theory of sequence-dependent properties of heteropolymers, several biomolecular condensates were observed experimentally to exhibit specificity in the absence of apparent structural order. In particular, we have previously reported experimental measurements indicating that condensates composed of the intrinsically disordered region (IDR) of the largest subunit of the transcriptional coactivator complex Mediator (MED1) partition-specific proteins, mediated by sequence patterns of charged amino acids on the disordered regions of both MED1 and the interacting protein partner. However, whether this specificity is due to an unknown ordered-structure-mediated interaction or arising mainly from the dynamic multivalent interactions between the patterned charged amino acids in the IDRs was not clearly resolved. Here, we show that a polymer physics model combining Flory-Huggins theory and random phase approximation that only accounts for sequence-dependent multivalent interactions among polymers in a statistical manner can largely explain published data on selective partitioning and make predictions that are subsequently experimentally validated. Utilizing our high-throughput approach (the code for which is publicly available) to systematically scan >160,000 protein sequences, we identified novel high-partitioning IDRs and experimentally confirmed their behavior, highlighting the utility of this model in identifying regions responsible for partitioning. While our approach accurately predicted partitioning for most sequences, discrepancies for certain IDRs with significant aromatic contents revealed the need to incorporate non-electrostatic interactions, such as multivalent cation-π interactions, to fully account for partitioning behavior in future developments of the method. Taken together, our results suggest that the specificity of condensate composition is underpinned to a substantial extent by multivalent interactions in the context of conformational disorder.
Wessén et al. (Sun,) studied this question.