We have developed a method for the prediction of an amino acid sequence tha
t is compatible with a three-dimensional backbone structure. Using only a b
ackbone structure of a protein as input, the algorithm is capable of design
ing sequences that closet!: resemble natural members of the protein family
to which the template structure belongs. Ln general. the predicted sequence
s are shown to have multiple sequence profile scores that are dramatically
higher than those of random sequences, and sometimes better than some of th
e natural sequences that make up the superfamily. As anticipated. highly co
nserved but poorly predicted residues are often those that contribute to th
e functional rather than structural properties of the protein. Overall, our
analysis suggests that statistical profile scores of designed sequences ar
e a novel and valuable figure of merit for assessing and improving protein
design algorithms.