Monte Carlo simulations of the folding of beta-barrel globular proteins.

With the use of dynamic Monte Carlo simulations, the necessary conditions for the collapse from a random-coil denatured state to a structurally unique four-member beta-barrel native state of a model globular protein have been investigated. These systems are free to roam through all of configuration space--both native and nonnative interactions are allowed. The relative importance of hydrophobic and hydrophilic interactions and the presence or absence of statistical bend-forming regions for the formation of a unique native state are examined, and the conditions necessary for a denatured-to-native (and vice versa) conformational transition that is thermodynamically all-or-none and which always results in collapse to the same, four-member beta-barrel are explored. These conditions are found to be a general pattern of hydrophobic/hydrophilic residues that allows the native state to differentiate the interior from the exterior of the protein and the presence of regions that are, at the very least, neutral toward turn formation. The former set of interactions seems to define the mean length of the beta-stretch, and the latter set serves to lock the native state into the lowest free energy state, the native conformation. These folding simulations strongly suggest that the general rules of protein folding are rather robust and that site-specific tertiary interactions are only involved in structural fine tuning. The conditions required for the formation of a structurally unique native state from a manifold of collapsed conformations that are originally quite close in energy is highly suggestive of a mechanism of protein evolution by means of random mutations. The implications of these folding studies for such a mechanism are qualitatively explored.