Dr. Philip Bryan and Dr. John Orban, both professors in UMBI's Center for Advanced Research in Biotechnology (CARB), report advances in their laboratories in understanding the fundamental roles played by specific amino acid sequences in protein folding.

Protein molecules are chains of amino acids that are capable of self-organizing into 3-dimensional shapes which determine specific biological functions. Self-organization of proteins is at the junction where the field of chemistry crosses into biology. The fundamental ways that the sequence of amino acids in a protein chain determine its structure remain poorly understood, however, despite the central importance of protein structure to biological function. .

In a pair of papers published in the Proceeding of the National Academy of Sciences (USA), Dr. Bryan and Dr. Orban and their laboratory colleagues describe the design of a set of model proteins in which the essential folding information resides within a minimal number of amino acids. The stability, binding function, and structures of these proteins are described.

The surprising results of these studies reveal that two different folds and two different functions can be encoded by changing only 5% of the amino acids in a protein (3 out of 56). This result is unprecedented, challenging many widely accepted ideas about how folding signals are encoded within amino acid chains.

These papers thus reveal a key element of the folding code. Essential folding information can be highly concentrated in a few amino acids and a very limited subset of interactions in the protein can tip the balance from one structure to another. This suggests a mechanism for the evolution of new proteins, involving small changes, which are not only probable but also perhaps inevitable.

References for the two published PNAS papers are:

Alexander, P. A. et al (2007) The design and characterization of two proteins with 88% sequence identity but different structure and function. Proc. Natl. Acad. Sci. USA 104, 11963-11968.

He, Y. et al (2008) NMR structures of two designed proteins with high sequence identity but different fold and function. Proc. Natl. Acad. Sci. USA 105, 14412-14417.