THERMO Peptide solubility guidelines

Thermo Scientific

The chemical and physical properties of peptides are dictated by their amino acid composition. Although some peptides easily dissolve in aqueous solutions, a common problem encountered is very low solubility or even insolubility, especially peptides with long sequences of hydrophobic amino acids. Known characteristics of individual amino acids (Table 1) can help to predict a peptide’s solubility. Furthermore, peptides shorter than five residues are usually soluble in water or aqueous buffer, except when the entire sequence consists of hydrophobic amino acids (e.g., W, L, I, F, M, V, Y).

Hydrophilic peptides containing > 25% charged residues (e.g., D, K, R, H and E) and 25% hydrophobic amino acids are usually soluble in water or aqueous buffers. Peptides containing 50% and more hydrophobic residues might be insoluble or only partly soluble in aqueous solutions. In this case, use organic solvents like dimethoxysulfoxide (DMSO), dimethylformamide (DMF) or acetonitrile (ACN).

Peptides containing a high proportion (> 75%) of D, E, H, K, N, Q, R, S, T, Y are capable of building intermolecular hydrogen bonds (i.e., crosslinking), thus forming gels in aqueous solutions. Treat these peptides according to the instructions for hydrophobic peptides or change the pH value, if possible. If the peptide is not soluble in solvents compatible with your biological assay, optimization of the peptide sequence is necessary. Shortening the sequence or adding hydrophilic or charged amino acids results in higher solubility. For assistance in peptide design please contact

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