Peptide solubility

Published on May 2nd 2023

We get asked about peptide solubility a lot, so we have updated our recommendations based on our most frequent questions.  Solubility is obviously very important in biochemical experiments, but peptide (and protein solubility) in aqueous solution varies widely, ranging from almost complete insolubility to solubility of hundreds of milligrams per millilitre.  Where possible we provide solubility instructions for dissolving individual peptides, which can be found on the data sheet for each individual product, but if specific instructions are not available, the following guidelines may be used:

Catalogue peptides:  Most peptides,  especially those of five or less amino acids, are soluble in distilled water. If they do not completely dissolve, the addition of 1.0 M acetic acid for basic peptides (those containing Arg, Lys, His) or 1.0 M ammonium hydroxide for acidic peptides (those containing Asp, Glu) may help. Solubilization of extremely insoluble peptides can be assisted with 10% DMSO or DMF, although the use of these co-solvents may interfere with some biological assays. Sonication can also be a useful aid for solubilizing peptides. When solubilizing peptides, it is recommended that the peptide be dissolved to the highest possible concentration, and then diluted with water or buffer to the required concentration. 

Peptide antigens:  When designing peptide antigens, bear in mind that the hydrophobicity of the amino acid constituent strongly influences the corresponding peptide solubility. Peptides with high incidences of hydrophobic amino acids, including tryptophan, leucine, valine, methionine, phenylalanine, and isoleucine may not easily dissolve in aqueous solutions. For peptide antigens, hydrophobic amino acid content is suggested to be kept below 50% with at least one charged residue incorporated within every five amino acids.   At physiological pH, arginine, glutamic acid, aspartic acid and lysine all have charged side chains. A single conservative replacement or addition of polar residues to the N- or C-terminus may also improve peptide solubility, but if the whole sequence is only hydrophobic amino acids the peptide will have limited solubility, or even be completely insoluble. Hydrophilic peptides that contain greater than 25% charged residues (Glu, Asp, Lys, Arg, and His) and hydrophobic peptides that consist of greater than 50% hydrophobic amino acids may be insoluble or only partly soluble in aqueous solutions.  However peptides with greater than 25% charged residues are not always insoluble - charge may determine the most appropriate aqueous buffer for peptide dissolution.  Multiple Arg, His and Lys constituents will require an acidic system, multiple Glu and Asps will require a basic one.

Hydrophobic peptides:  Hydrophobic peptides that contain greater than 75% hydrophobic residues do not easily dissolve in aqueous solutions. Instead, strong solvents, such as TFA or formic acid, must be used for the initial solubilization step.  These peptides may precipitate when added to buffered aqueous solutions, and if this occurs, high concentrations of organic solvent or denaturants may be required to dissolve them.  Peptides that include a very high percentage (greater than 75%) of Glu, Asn, His, Lys, Gln, Arg, Ser, Trp, Phe and Thr residues can form cross linking intermolecular hydrogen bonds and so they may form gels in concentrated aqueous solutions.  It is often the amphipathic nature of the peptide which causes hydrogel formation and if this occcurs these peptides may be melted by gentle heating or may be dissolved in organic solvents.  It is important that the initial solvent selected is compatible with the final experiment.  Once the peptide has been dissolved in organic solvent, the solution should be added dropwise to the stirred aqueous buffer solution. If the resulting solution begins to become turbid, the solubility limit has been reached.

If you have any questions at all about how to dissolve a peptide, or how we would recommend that antigen sequences are designed, please don't hesitate to contact us.

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