A New Approach to the Design of Uniquely Folded Thermally Stable Proteins

X. Jiang, H. Farid, E. Pistor and R. S. Farid

Protein Science, 9:403-416, 2000

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A new computer program (CORE) is described that predicts core hydrophobic sequences of predetermined target protein structures. A novel scoring function is employed that for the first time incorporates parameters directly correlated to free energies of unfolding ( D G_u ), melting temperatures (T_m ) and cooperativity. Metropolis-driven simulated annealing and low-temperature Monte Carlo sampling are employed to optimize this score, generating sequences predicted to yield uniquely folded stable proteins. The hydrophobic core residues of four natural proteins were predicted using CORE. In the two smaller proteins tested (Gb1, 11 core amino acids; 434 cro, 10 core amino acids), the native sequence was regenerated as well as the sequence of known thermally stable variants. As importantly, designed sequences of variants know to exhibit lower thermal stability and weaker cooperativity were not predicted. In the two larger proteins tested (myoglobin, 32 core amino acids; methionine aminopeptidase, 63 core amino acids) sequences remarkably similar to the native were predicted.