Aromatic tripeptide predicted insoluble displays highest known solubility

Despite the fundamental importance of solubility, this key physical property remains only partially understood, and its prediction often fails to reproduce experimentally measured values. Here, we systematically investigate the solubility of aromatic amino acids and their dipeptides to hexapeptide oligomers. Remarkably, tyrosyl-tyrosyl-tyrosine tripeptide (YYY) exhibits an unprecedented solubility of ∼10,090 mg/mL, nearly five orders of magnitude higher than its monomeric counterpart (∼0.5 mg/mL), approximately 21 times higher than glucose (∼479 mg/mL) and 13 times higher than fructose (∼778 mg/mL), thereby establishing YYY as the most soluble organic solid reported. Chemical modification of YYY termini significantly reduces its solubility, indicating the native structure singularity. The remarkable solubility of a simple peptide allows the development of highly soluble organic materials with applications across science and engineering.