Protein Design by Optimization of a Sequence-Structure Quality Function

An automated procedure for protein design by optimiza-tion of a sequence-structure quality has been developed. The method selects a statistically optimal sequence for a particular structure, on the assumption that such a protein will adopt the desired structure. We present two optimi-zation algorithms: one provides an exact optimization while the other uses a combinatorial technique for com-paratively rapid results. Both are suitable for massively parallel computers. A prototype system was used to design sequences which should adopt the four-helix bundle conformation of myohemerythrin. These appear satisfactory to secondary structure and profile analysis. Detailed inspection reveals that the sequences are gener-ally plausible but, as expected, lack some specific struc-tural features. The design parameters provide some insight into the general determinants of protein structure