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Peptide Solubility – How To Solubilize A Peptide

Peptide Solubility

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Peptide Solubility – How To Solubilize A Peptide

Peptides are chemical structures composed of two or more amino acids that are linked together in short chains by amide bonds. They occur naturally, but it is also possible to create them through peptide synthesis for various research, medical, and production purposes. Many companies that supply synthetic peptides subject them to the lyophilization process, which involves freeze-drying them and sublimating any liquid content to preserve and stabilize them for transport purposes. Peptides obtained in the freeze-dried form must be reconstituted in appropriate peptide solutions before they are ready for use. For this, it is important to know about peptide solubility.


What Is Peptide Solubility?

Peptide solubility is the ability of peptides to solubilize in water or other solutions. The peptide solubility is evident in the appearance of the solution. A transparent solution indicates the solubility of amino acids, while a cloudy solution indicates a hydrophobic peptide. While many peptides can dissolve easily in distilled water solutions, many hydrophobic peptides may have low aqueous solubility or may even be insoluble. 

Researchers and manufacturers need to know which peptide solvents will work best for their specific purpose before they begin work on any new application. Otherwise, they might encounter solubility issues that could hamper their work and compromise the quality of the peptides or ruin them completely.

What Are the Factors that Determine Peptide Solubility?

The peptide solubility factor depends on the physical properties of its amino acids and the peptide environment. It is possible to make a peptide solubility prediction based on these factors. For example, when it is necessary to know whether peptides are water soluble researchers can determine if the peptides are hydrophilic or hydrophobic. For this, studying the sequence of the amino acids that form the peptides is essential. Amino acids can be acidic, basic, and neutral, with the latter having polar residues and non-polar or hydrophobic residues.

The residues with higher ionic charges tend to be more soluble, and these charges are generally higher at pH 6-8. This rule excludes hydrophobic and aggregator peptides. Those made up of acidic amino acid chains are soluble in basic solvents like ammonium hydroxide or ammonia water. Peptides with basic amino acids require acidic solvents like acetic acid solution. Organic solvents like dimethylformamide, dimethyl sulfoxide, methanol, or propanol can solubilize neutral amino acids. If there are dispersed proline residues, they can increase peptide solubility with their ability to disrupt secondary structures.

How to Determine Net Charge of a Peptide

It is possible to determine the net charge of a peptide by identifying all ionizable groups. These can include the N-terminal’s amino group, the C-terminal’s carboxyl group, and the ionizable groups in the amino acid side chains. Follow these steps:

  • Designate each acidic residue with -1 value:
  • Designate each basic residue with +1 value;
  • Designate each Histidine residue with a pH less than six with +1 value;
  • Designate each Histidine residue with pH greater than six with a zero value;
  • Count the peptide charges when the pH is neutral at seven; and
  • Add together the peptide charges.

The sum of the peptide charges is useful for determining the following:

  • If the charges are less than zero, the peptide is acidic and needs solubilization in a basic solution;
  • If the charges are more than zero, the peptide is basic and requires an acidic solvent;
  • If the charged residues exceed 25%, the peptide is neutral and dissolves in water or aqueous solutions; and
  • If the charged residues are less than 25%, the peptide is neutral and hydrophobic and requires organic solvents.

What Is the Solubilization Procedure for Peptides?

Generally, companies that supply peptides will provide an accompanying detailed data sheet about the specific solvent to use. It is advisable to use the recommended solvent if it suits the required application. Otherwise, it is best to allow peptides to reach room temperature and then use a small peptide sample to test their solubility first in distilled water and then in other solvents. It is essential to select an initial solvent that the lyophilization process can easily remove. So, in case the solubilization procedure does not work, it will be possible to remove the peptide intact from the solvent.

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