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Bavidra Kulendrarajah What determines the three dimensional structure of a protein? What types of chemical interactions are involved? What do the different properties of these interactions contribute to the overall structure? What are protein domains? What is the importance of this form of organisation of protein structure?
The tertiary structure of a protein describes the folding of a polypeptide chain into a three dimensional structure which is created when parts of the polypeptide chain remote in sequence is brought close together. It is formed by packing secondary structures such as alpha helices, beta pleated sheets and loops into several compact globular units known as domains. The folding of the chain gives the protein a precise shape which is essential as it determines the function of the protein in a cell. The majority of the proteins have a complex, irregular structure and this allows the proteins to recognise many other molecules by three dimensional interactions. If the three dimensional shape of a protein is lost due to an increase in temperature or changes in pH, it results in the protein becoming denatured and losing its function. This means that a denatured enzyme loses its catalytic activity whilst an antibody loses its ability to bind to an antigen. What determines the three dimensional structure of a protein?
The three dimensional structure of a protein is determined by the sequence of amino acids in the polypeptide chain. This was shown using the enzyme ribonuclease which is a single polypeptide chain consisting of 124 amino acids that is cross linked by four disulfide bonds. When urea is added to the protein it breaks the van der Waals' forces between the amino acids and results in the loss of the protein's tertiary structure. However when the solution of urea is removed the polypeptide is able to randomly coil into its orginial three dimensional structure and regain its catalytic activity without any external forces. This shows that the amino acid sequence contains all the information that is needed for a protein to refold spontaneously into its original conformation. There are twenty amino acids each with differing R groups (side chains). It is these side chains which can be hydrophobic, charged or polar that determine the properties of the twenty amino acids and also determine the type of weak non covalent bonds that occur between them. Due to the interactions that occur between the side chains of the amino acids the protein is folded into a single stable three dimensional conformation. However when the protein interacts with other molecules in the cell it results in the conformation of the protein changing slightly which shows that the forces that hold the tertiary structure of a protein are not rigid. What types of chemical interactions are involved? What do the different properties of these interactions contribute to the overall structure?
The folding of a protein into its three dimensional structure is determined by the combination of weak non covalent bonds that occur between the side chains of amino acids in the polypeptide chain. There are four main types of weak non
Bavidra Kulendrarajah covalent bonds: hydrogen bonds, electrostatic attractions, van der Waals and hydrophobic interactions. It is the combined strength of these non covalent forces that results in the stability of the folded shape of a protein. Hydrogen bonds are formed between a hydrogen atom that is covalently bonded to an electronegative atom and a second electronegative atom. In proteins hydrogen bonds can either occur between the polar side chains of the amino acids or between the atoms that are involved in the formation of a peptide bond which results in the formation of secondary structures such as alpha helices and beta sheets. Individual hydrogen bonds are very weak but the total number of hydrogen bonds that occur between the side chains of amino acids is strong and so contributes to the stability of the tertiary structure. Another important role of hydrogen bonds is that it imposes geometrical constrictions and keeps the shape of the protein fairly fixed. This is because for maximum stability to occur in hydrogen bonds the three atoms that are involved in the formation of a hydrogen bond must be aligned in a straight line and the distance between the amino acid side chains must be kept to a minimum. Also when the hydrogen bonds occur between the side chains of amino acids it leads to the folding of the protein and this reduces the number of hydrogen bonds that occur between the side chain of an amino acid and water molecules. This is important because if the amino acid forms hydrogen bonds with water it reduces the energetic contribution of the amino acid to its structural and binding properties of protein. The second force that occurs between side chains of amino acids are electrostatic forces or otherwise known as ionic interactions. There are three major types of electrostatic interactions found in the protein structure; charge-charge, chargedipole or dipole-dipole. One example of charge to charge electrostatic attraction is present between negatively charged side chains such as in aspartate and between positively charged side chains found in arginine. The strength of the interaction is determined by the magnitude of the charges found on the side chain, the distance between the side chains and the extent to which the side chains interact with water. As the majority of the polar side chains are arranged so that they are exposed to the aqueous medium it results in the weakening of the electrostatic interactions. This is because the polar water molecules cluster around both the charged ions found in the side chains and this results in the weakening of the attractive force between the oppositely charged amino acids. However, if the interactions occurred in a less polar medium the forces would be stronger. These interactions are important in protein folding as they are effective over long ranges, therefore are useful for protein-protein or protein-ligand interactions.
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