Peptide solubility basics: how sequence decides what dissolves

Count the charge

Assign +1 to each lysine, arginine and the free N-terminus, and -1 to each aspartate, glutamate and the free C-terminus. A clearly positive peptide tends to dissolve in slightly acidic solutions, a clearly negative one in slightly basic solutions. The peptide mass calculator reports charge and isoelectric point from a sequence.

Look at hydrophobic content

Peptides in which more than about half the residues are hydrophobic (leucine, valine, isoleucine, phenylalanine, tryptophan) often resist aqueous solvents and may need an organic co-solvent.

The isoelectric point

Peptides are least soluble near their isoelectric point, where net charge is zero. Moving the pH away from it usually helps.

Practical cautions

Supplier documentation takes priority over general rules for a given product.

• Test a small amount before committing the whole vial.
• Oxidation-prone residues (Cys, Met, Trp) can limit solvent choices.
• Aggregation can look like cloudiness; filter or discard rather than assuming it will clear.