This is an interesting article that I actually stumbled across a citation to while reading a book (Genetics and the Logic of Evolution, Kenneth Weiss and Anne Buchanan). It is several years old now. "Functional proteins from a random-sequence library." Keefe, A.; Szostak, J. Nature, 2001, 410, 715-718. The authors were interested in how frequently a random library of peptides would include a useful protein. In order to test this they made a humongous library of peptides linked to their mRNAs. They converted the mRNAs to DNAs, ran the DNA/protein complex through ATP-agarose to find those that bound ATP, amplified these by PCR, and repeated the process. After eight rounds of this they had 6.2% of the proteins binding ATP. These were found to belong to four different families, each originating from one ancestor protein present in the random pool, and had no resemblence to existing ATP-binding proteins or other proteins. These were then subjected to error-prone PCR to mutate the proteins further. After six more rounds of mutagenesis the ATP-binding fraction rose to 34%. In this process three of the four original families were wiped out, and all proteins present belonged to one of the original families. This is interesting--none of the other proteins had this zinc-binding motif. They did not add zinc to the selection buffer, but said that it was present in low levels in mammalian blood which they used to prepare the lysate to translate the mRNAs. They think this indicates that metal chelation provides an easy way to induce folding in simple proteins. Thank goodness that's not me.