A universal code for phase separation of prion-like low complexity domains: Insights from quantitative computer simulations.

Abstract

Biomolecular phase separation is a critical mechanism that contributes to intracellular spatiotemporal organization via the formation of biomolecular condensates. In addition to their widespread implications in aggregation-related disorders, prion-like low complexity domains (PLCDs) have been shown to exhibit demixing behavior and their aberrant condensation has been linked to disease. Here, we investigate the relationship between amino acid sequence and phase behaviour of the PLCDs exploring an unprecedented set of 140 different protein sequences. To this end, we perform direct coexistence molecular dynamics simulations of our residue-resolution coarse-grained protein model, which we have shown accurately predicts quantitative phase diagrams. For variants where experimental phase behaviors have been characterized, we show that our predictions are in excellent agreement with the experimental results. Analysis of the full simulation set of 140 variants reveals that the identity and patterning of sticker residues (e.g., Y, F) are crucial to define the phase behaviour of PLCDs. Notably, aromatic and charged residues have context-dependent effects on the critical temperature of PLCD condensation. Regarding spacer residues (e.g., S, G, N, T), PLCDs condensates are remarkably stable in front of mutations of glycine and serine but are more sensitive to mutations of asparagine and glutamine. Remarkably, these results extend to the entire family of PLCDs tested and, therefore, reveal universal codes for PLCDs phase behavior. Furthermore, the findings here help shed light on the functions of PLCDs and aid in the design of modifications to counter their aberrant phase separation.