We replaced an essential RNA-binding, 30-amino acid helix-loop in an Escherichia coli tRNA synthetase with an inactive and simplified "generic" sequence having 23 of the 30 amino acids as alanine and serine. Wild-type residues were restored in random combinations to generate a library with a sequence complexity of about 1.9 x 10(7). Active molecules were obtained by genetic selection at a frequency of approximately 1% and contained variants with as many as 11 alanine/serine replacements and a total of 17 alanine/serine residues. These variants have activities which are thermodynamically competitive with that of the native protein and therefore are functionally and, most likely, conformationally equivalent.