Fig. 4.

Hierarchic organization of proteins. In a hierarchy, each component is contained within the next larger component, like a series of nested boxes. Hierarchic architecture, illustrated here for ribonuclease, can be verified easily for any protein of known structure by using a simple procedure: display the structure with the first N/2 residues in magenta and the remaining N/2 residues in cyan. Then repeat this procedure, iteratively. It is apparent at a glance that at each successive level of the hierarchy, magenta and cyan regions do not intermingle. (Surface shown in gray is a place holder.) This top-down, hierarchic architecture is an experimental fact, and no hypothesis is needed to extract this result from known structures. Hierarchy suggests a bottom-up folding mechanism (40, 56, 57) in which chain segments form local structures of marginal stability, which then interact iteratively to produce intermediates of ever-increasing complexity. In this process, multiple folding routes coexist, and the stabilities of intermediates and their combinatorial associations determine the dominant pathways (49). Picture was rendered by using Pymol (127).