Charged amino acid propensities and solubility: lysine is elevated at the termini of helices in E. coli proteins.

An emerging result in the relationship between amino acid sequence and protein solubility is a preference, on average, for lysine over arginine in more soluble proteins. The termini of helices are known to be prone to partial unfolding, often employing N- and C-cap amino acids to maintain stability. Hypothesising that lysine/arginine differences in relation to solubility may be evident at helical termini, their propensities and predicted charge interactions in helices were examined. There is enrichment of lysine over arginine at helical termini in AlphaFold models of Escherichia coli proteins, more so (on average) for the most soluble proteins. Similar effects are seen for the sum of charged amino acids at helical termini. Regions other than helical termini also show correlation of lysine composition, and overall charged amino acid composition, with solubility. These results suggest that protein design protocols could improve solubility through targeting lysine enrichment in regions such as helical termini, in addition to the more conventional consideration of helix capping interactions.