Computer modeling and folding of four-helix bundles.

In the context of simplified models of globular proteins, the requirements for the unique folding to a four-helix bundle have been addressed through a new Monte Carlo procedure. In particular, the relative importance of secondary versus tertiary interactions in determining the nature of the folded structure is examined. Various cases spanning the extremes where tertiary interactions completely dominant to that where tertiary interactions are negligible have been explored. Not surprisingly, the folding to unique four-helix bundles is found to depend on an adequate balance of the secondary and tertiary interactions. Moreover, because the simplified model is composed of spheres representing alpha-carbons and side chains, the geometry of the latter being based on small real amino acids, the role played by the side chains, and the problems associated with packing and hard-core repulsions, are considered. Also, possible folding intermediates and their relationship with the experimentally observed molten globule state are explored. From these studies, a general set of rules is extracted which should aid in the further design of more detailed protein models adequate to more fully investigate the protein folding problem. Finally, the relationship between our conclusions and experimental work with specifically designed sequences is briefly discussed.