Deciphering the chemical grammar of protein-RNA condensates

TL;DR

This study uncovers how specific chemical interactions between short peptides and nucleobases influence protein-RNA condensate formation, revealing a chemical grammar underlying phase separation.

Contribution

It demonstrates that ultrashort peptide units encode phase separation instructions and that nucleobases act as chemical tuners, advancing understanding of biomolecular condensate regulation.

Findings

Ultrashort dipeptides can spontaneously condense, indicating a sub-polymeric level of phase separation.

Nucleic acids influence condensates through base-specific interactions, not just as generic anionic agents.

Nucleobases can dissolve, stabilize, or fluidize condensates depending on their molecular identity.

Abstract

Biomolecular phase separation is typically attributed to the polymer physics of long, disordered chains. However, the underlying chemical grammar, i.e. the specific interactions between protein and RNA building blocks, remains poorly understood. We decouple those effects by screening the phase behavior of the complete dipeptide library in presence and absence of nucleic acids using full-atomistic molecular dynamics simulations. We demonstrate that (i) even these ultrashort units encode the instructions for spontaneous condensation, proving that phase separation is fundamentally rooted at a sub-polymeric level. (ii) Nucleic acids do not act as generic anionic glue but exert instead a base-specific regulatory logic. (iii) Individual nucleobases function as chemical tuners that dissolve, stabilize, or fluidize condensates based on their molecular identity. Overall, our minimal framework reveals that while polymer length enhances assembly, the core properties and regulatory control of condensates may be also governed by a fine-tuned chemical alphabet of peptides and nucleobases.