FUNCTIONAL RAPIDLY FOLDING PROTEINS FROM SIMPLIFIED AMINO-ACID-SEQUENCES

Early protein synthesis is thought to have involved a reduced amino ac id alphabet. What is the minimum number of amino acids that would have been needed to encode complex protein folds similar to those found in nature today? Here we show that a small beta-sheet protein, the SH3 d omain, can be largely encoded by a five letter amino acid alphabet but not by a three letter alphabet. Furthermore, despite the dramatic cha nges in sequence, the folding rates of the reduced alphabet proteins a re very close to that of the naturally occurring SH3 domain. This find ing suggests that despite the vast size of the search space, the rapid folding of biological sequences to their native states is not the res ult of extensive evolutionary optimization. Instead, the results suppo rt the idea that the interactions which stabilize the native state ind uce a funnel shape to the free energy landscape sufficient to guide th e folding polypeptide chain to the proper structure.