Why are proteins three-dimensional

Martin Luther University Halle-Wittenberg

All over in living systems molecular structures self-assemble with high precision. The associated folding of molecular chains of amino acids into proteins depends on the amino acid sequence (“primary structure”) and the various influences of the crowded environment in the cell in our body. This complex folding process from an unstructured polypeptide chain to a specific three-dimensional protein structure has up to now not fully been understood.

The resulting highly specific structures are connected to certain biological activities and biochemical processes, such as the positioning of molecules at a specific location inside the cell or the regulation of cellular growth. Only correctly folded proteins are able to interact selectively with their natural partners and to fulfill their intrinsic functions. On its way to the thermodynamically most stable state, (which is preferably the native state), the polypeptide chain stochastically samples through the accessible conformations. On average, native-like interactions between residues of the amino acid sequence are more stable than others. This higher persistence enables the protein to fold rapidly during its transition from a random coil to a native structure via sampling through only a small number of all possible conformations.

Figure 1: Structural model of a protein (bromoperoxidase A2) with its secondary structure: α-helices (red) and β-sheet (blue). The β-sheets consist of several β-strands connected by β-turns. (structure data of 1BRO taken from PDB)

The folding process occurs at different time scales. Whereas individual α-helices and β-turns are typically able to form in less than 100 ns and 1 µs respectively, particularly those proteins composed of β-sheet structures can take many orders of magnitude longer to fold. These helices and sheets (“secondary structure”), see Figure 1, can be found in nearly every protein structure and are general, three-dimensional structural motifs of the protein. They are stabilized primarily by hydrogen bonds. These bonds are specific interactions - often not existing in synthetic polymers - between the carbonyl group of one amino acid and the amino group of another.

The function of a protein depends on its three-dimensional structure. This arrangement of the secondary structure elements in space is termed “tertiary structure”. The wide ranging consequences of incorrectly folded proteins, or proteins with only a short-term stability of the native state are obvious.