Monte Carlo simulation of equilibrium globular protein folding: alpha-helical bundles with long loops

To help elucidate the general rules of globular protein folding, computer simulations of the conformational transition in model proteins having the left-handed, four-helix bundle motif in which the helices are joined by one or two long loops, as in apoferritin and somatotropin, respectively, have been undertaken. In the context of simple tetrahedral lattice protein models, these unique native helix bundle motifs can be obtained by a set of interactions similar to those found in previous simulations of the folding of four-member alpha-helical bundles with tight bends and beta-barrel proteins including the Greek key motif. The essential features sufficient to produce the four-helix bundle motif with long loops are as follows: (i) a general pattern of hydrophobic and hydrophilic type residues which differentiate the interior from the exterior of the molecule; (ii) the existence of hydrophilic regions in the amino acid sequence that, on the basis of short-range interactions, are indifferent to loop formation but that interact favorably with all the exterior residues of the helix bundle. Thus, these simulations indicate that, to reproduce all varieties of the left-handed four-helix bundle motif, site-specific interactions are not required.