Principles of Protein Structure - H. Schulz 1982

Modes of folding and association of polypeptide chains
Hierarchy of levels

Hierarchical relationships greatly facilitate analysis. The Levels of Protein structural Organization and their hierarchical scheme are shown in Fig. 5.1. Following this scheme, the Analysis of the folding process is considerably simplified, as it breaks down into several distinct stages (comparable to factorization when solving differential equations). Thus, in The First stage, the Secondary Structure is to be deduced from the Amino Acid Sequence; In the second, the supersecondary structure is determined from the secondary structures, and so on. However, tempting as it may be to approach the protein folding problem in this manner, the reality is far more complex, and the proposed scheme is likely applicable in only a few cases.

The Hierarchy of Protein structural levels does not hold in many instances. This hierarchy was originally established using Globular Proteins and their aggregates as Examples. Indeed, in most cases, a globular monomer is quite stable and remains virtually unchanged upon aggregation*; consequently, the complex structure is essentially determined by the surface CHARACTERISTICS OF THE established monomeric structure. This approach was successfully applied to The Study of sickle-Cell Hemoglobin [270]. However, hierarchical dependencies do not apply to Ribosomes. Ribosomal proteins are so elongated [7] that The structure of each individual unit is unstable and is stabilized only through the aggregation process.

Hierarchy is also exhibited by the levels corresponding to The amino acid sequence and secondary structure (especially a-helices), since The formation of the secondary structure strongly depends on the final folding of the chain. This Conclusion follows from the observed correlations between the amino acid sequence and secondary structure described in the next chapter.

* A detailed analysis of small changes upon the association of Trypsin and bovine pancreatic trypsin inhibitor was performed by Huber et al. [269].

The association of domains in multidomain globular proteins also appears to be hierarchical in nature. In particular, the predominant single-chain articulation of sequentially arranged domains and the observed symmetrical arrangement of domains indicate that domains are formed prior to their association within the protein globule and that they are highly stable on their own.

The transition from secondary to supersecondary structure, and from supersecondary structure to domains, is less clear. Of all secondary structures, only $\alpha$-helices are sufficiently stable and can form completely prior to the subsequent association stage. However, isolated $\beta$-pleated sheets and reverse turns do not exhibit such properties. As for Supersecondary structures, the Symmetry discovered in A number of domains suggests that supersecondary structures are sufficiently stable in their own right and constitute a distinct level of protein organization.