IMPROVED DESIGN OF STABLE AND FAST-FOLDING MODEL PROTEINS

Background: A number of approaches to design stable and fast-folding s equences for model polypeptide chains have been based on the premise t hat optimization of the relative energy of the native conformation (or Z-score) is sufficient to yield stable and fast-folding sequences. Al though this approach has been successful, for longer chains it often y ielded sequences that failed to fold cooperatively, instead having mul tidomain folding behavior. Results: We show that one of the factors de termining single-domain or multidomain folding behavior is the dispers ion of energies of native contacts. So, we study folding of sequences optimized to have the same native conformation as a global energy mini mum but having different dispersion of native contact energies, Our re sults suggest that under conditions at which native conformation is st able, the best-folding proteins are those that have smaller heterogene ity of native contact energies. For them, the folding transition is al l-or-none. On the other hand, proteins with greeter heterogeneity of n ative contact energies have more gradual multidomain folding transitio n and fold into stable native conformation much slower thin those prot eins with small dispersion of native contact energies. Conclusions: Th ese results give further guidance for the design of stable, fast-foldi ng and cooperatively folding sequences.