Stoichiometry and Preferential Interaction: Two Components of the Principle for Protein Structure Organization

Abstract

by Mittal and coworkers proposed an interesting view that protein folding is driven by the stoichiometry of amino acids rather than by the “preferential interactions” between them (1). By analyzing about 3700 backbones of folded proteins, the authors argued that something like Chargaff’s rules exist in protein folding similarly as in the orga-nization of DNA structures. The above conclusion was made by counting the numbers of contacts between two specific residues at a variable range of neigh-borhood distance and by showing that they all follow a similar sigmoid trend and the total number of contacts formed by one residue is excellently correlated with the percentage occurrence of that residue. The authors' conclusion highlights the importance of amino acid composition in the determination of protein folding as well as in the organization of the folded protein structures. This is generally true and in line with some previous reports where the correlation between protein folding rates and the amino acid composition was found as high as 0.7 (2) and the prediction accuracy of protein folding type (two-state or multi-state folding) based merely on the occurrence numbers of amino acids could be more than 80% (3). Considering the limited information (only the frequencies of amino acids) used in the predictions, the achieved accuracy is surprising. All these results emphasized the important roles played by the stoichiometry of amino acids in protein folding.However, the above results are not a reason to deny the roles played by preferen-tial interactions of amino acids in the organization of protein structures. A wealth of evidence showed that the protein functional conformations are accomplished by particular arrangement of amino acids. Firstly, the neighborhood occurrence of amino acids in the primary sequence is not random (4). Secondly, it is well known that amino acids preferentially occur in different types of secondary structures (α-helix, β-sheets and coils,