Two Amino Acids Are Enough For Making Active Proteins

The 20 standard amino acids found in nature provide the chemical diversity needed to make the proteins that carry out the functions of life. Scientists at Yale University decided to look at protein design from a different perspective: They wanted to know how little chemical diversity a protein could contain and still be biologically active. To find out, Daniel DiMaio, Donald M. Engelman, Erin N. Heim, and coworkers constructed a library of proteins only 26 amino acids long with random sequences of just leucine and isoleucine—amino acids that differ only in the position of a methyl group. The researchers screened the library for growth-promoting activity in mouse cells and identified sequences that activate platelet-derived growth factor β-receptor (Proc. Natl. Acad. Sci. USA 2015, DOI: 10.1073/pnas.1514230112). Despite the minimal chemical diversity, the researchers were able to identify preferences for amino acids at certain locations. For example, most of the active sequences contain isoleucine at position 13, which the researchers think may be interacting specifically with the receptor. “It seems that even with two very similar amino acids, what’s important is the sequence,” DiMaio says. “The diversity comes from the order of the residues and not at all, or very little, from the chemical diversity of the side chains.”