The most important component of structure in determining a protein’s function is the next level of folding, termed the tertiary structure. The whole polypeptide chain, including elements of defined secondary structure, is folded into a unique three-dimensional configuration. There would seem to be an almost limitless variety of tertiary structures that can be formed by polypeptide chains of different sequence. A few examples are shown in Figure 1. In recent years, it has become possible to determine such structures, often to atomic detail, by the techniques of X-ray diffraction (Box 3.6) and multidimensional nuclear magnetic resonance (NMR) (Box 3.7). To date, thousands of structures have been determined and can be found in publicly available protein data banks. The question that must be asked is: if so many structures are possible, why does each protein have a unique one?
Fig1. Gallery of protein structures. The convention used here employs ribbons to represent secondary structures that are twisted into α-helices or that lie parallel or antiparallel in β-sheet structures; thin lines represent regions that do not have a simply defined secondary structure. [B, courtesy of Chung-Eun Ha, University of Hawaii at Manoa, Honolulu, HI, USA. C, courtesy of the Research Collaboratory for Structural Bioinformatics.]
The specific tertiary structure that a protein will adopt is dictated by noncovalent inter actions, primarily between side chains but also with the surrounding water molecules. Characteristics of these interactions are given in Table 1. Of equal importance is the fact that hydrophobic residues tend to pack into the core of the molecule, away from water; this is known as the hydrophobic effect (Figure 2). The hydrophobic effect is not truly a force, like van der Waals interactions, but a consequence of the effect of hydrophobic groups on water structure. If inserted into water, they tend to arrange surrounding water molecules into rigid cages. Taking hydrophobic groups out of water into a protein interior releases these water molecules into their natural freedom. The increase in entropy associated with such freedom drives hydrophobic residues into the interiors of proteins. Hydrophilic residues, on the other hand, tend to be located on the surface of the protein molecule, in contact with surrounding water molecules (Figure 2). A very important consequence of these interactions is that the primary structure—that is, the amino acid sequence—dictates both the secondary and tertiary structure of each protein molecule. Thus the enormous diversity of protein structures is a direct consequence of the enormous number of possible sequences and will be determined by whatever determines those sequences. Today, we know that the DNA sequence of each protein-coding gene determines the protein sequence. In some cases, the secondary or tertiary structure of a protein may be modified by interactions with small molecules or other macromolecules. For example, we note that the ionic composition of the medium may promote conformational changes, as can the binding of certain small molecules, known as allosteric modulators (effectors) (Box 3.8). Even changing the protein environment around a particular sequence may cause that sequence to adopt a different secondary structure, as for so-called chameleon sequences in proteins. Finally, chemical modification of the protein side chains can affect conformation. However, because the structure of the protein defines and allows these interactions, the genetic information is still dominant.
Table1. Molecular interactions determining protein secondary, tertiary, and quaternary structure.
Fig2. Distribution of hydrophilic and hydrophobic residues in sperm whale myoglobin. (A) Distribution in sequence: note the two types seem to be randomly scattered. (B) Distribution in tertiary structure. Hydrophilic residues, shown in red, are mainly on the surface, in contact with water, while hydrophobic residues, shown in green, are largely buried. [Adapted from Mathews CK, van Holde KE, Appling DR et al. (2013) Biochemistry, 4th ed.]
