Monte Carlo Studies on Equilibrium Globular Protein Folding. 11. P-Barrel Globular Protein Models

In the context of dynamic Monte Carlo simulations on a model protein confined to a tetrahedral lattice, the interplay of protein size and tertiary structure, and the requirements for an all-or-none transition to a unique native state, are investigated. Small model proteins having a primary sequence consisting of a central bend neutral region flanked by two tails having an alternating hydrophobicfiydrophilic pattern of residues are seen to undergo a continuous transition to a /?-hairpin collapsed state. On increasing the length of the tails, the 8-hairpin structural motif is found to be in equilibrium with a four-member 8-barrel. Further increase of the tail length results in the shift of the structural equilibrium to the four-member /?-barrel. The random coil to 8-barrel transition is of an all-or-none character, but while the central turn is always the desired native bend, the location of the turns involving the two external strands is variable. That is, B-barrels having the external stands that are two residues out of register are also observed in the transition region. Introduction into the primary sequence of two additional regions that are a t the very least neutral toward turn formation produces an all-or-none transition to the unique, native, four-member 8-barrel. Various factors that can augment the stability of the native conformation are explored. Overall, these folding simulations strongly indicate that the general rules of globular protein folding are rather robust-namely, one requires a general pattern of hydrophobicfiydrophilic residues that allow the protein to have a welldefined interior and exterior and the presence of regions in the amino acid sequence that at the very least are locally indifferent to turn formation. Since no site-specific interactions between hydrophobic and hydrophilic residues are required to produce a unique four-member 8-barrel, these simulations strongly suggest that site specificity is involved in structural fine-tuning.