Enrichment of charge-absent regions in phase separated proteins

Many studies focus on the relationship between protein charge and liquid-liquid phase separation (LLPS), generally finding that a large degree of charge neutralisation is involved for condensate formation. Here, sequences within human proteins that lack the charge-bearing residues Asp, Glu, Lys, and Arg (termed charge-absent) are analysed alongside annotation for involvement in LLPS. Scaffold proteins, central to condensate formation, on average possess longer charge-absent regions than those not key for LLPS. Charge-absent regions tend to have relatively high hydropathy scores. Overall, they are enriched in Ala, Gly, Pro, and Ser with more specific groupings evident when the subset is clustered by amino acid composition. For several proteins, segments with charge-absent regions have been identified as modulators of LLPS. It is hypothesised that for at least some of the charge-absent regions, a lack of charged group desolvation energy, together with a relatively hydrophobic sequence composition, may facilitate condensation through homomeric interactions. If this is the case, it should be relatively easy to modulate through incorporation of charge through engineering, potentially including pH-sensing.