1.6.2 Determining the shape
During your studies you will meet a number of words which have Latin or Greek roots and whose meaning you may be able to work out. Coming up very soon are the words ‘hydrophobic’ and ‘hydrophilic’. You probably recognise hydro- as being related to ‘water’ (it is from the Greek word for water), since it occurs in words like hydroelectric, hydrothermal, hydroponics, hydrostatic, etc. Even the element hydrogen was named because it was originally generated (genos in Greek means ‘descent’) from water. The second half of the words, -phobic and -philic, mean ‘hating’ and ‘beloved’, respectively, from the Greek words phobos which means ‘fear’ and philos,‘friend’. As you read on, you will meet disulfide – where di-means ‘two’ (from the Greek dis meaning twice) and -sulfide means related to the element sulfur. You have already met carbon dioxide (a gas made up of one carbon and two oxygen atoms) and dipeptide, two amino acid molecules joined together. Sometimes the Latin prefix bi- is used as an alternative for ‘two’ as in bicycle, binoculars, etc. Tri-means ‘three’ (the Latin and Greek roots are similar), as in tripod (podos is ‘foot’ in Greek), and poly- (as in polypeptide) means ‘many’ (polys is ‘much’ in Greek).
The way in which each particular protein molecule folds is determined by a range of different interactions between the amino acids that make it up. Four of the most important ones will be considered here.
Firstly, some of the side chains of the amino acids – the R groups – a few of which were listed in Table 5 are hydrophobic, that is, they tend to associate with one another and to repel (or exclude) water molecules. The side chain of phenylalanine, containing the benzene ring, is one example. Since the inside of the body provides a watery (aqueous) environment, the protein chain folds up with these hydrophobic groups clustered together on the inside, and the hydrophilic groups on the outside, as shown in Figure 7.
Secondly, some of the amino acid R groups carry a positive or negative electrical charge, written as + or − , on one of their atoms. Opposite charges ( + and −) attract one another, and similar charges repel each other. These attractions and repulsions, called ionic interactions since the charged molecules are called ions, play a part in determining the shape that the protein adopts.
From Table 5, identify two amino acids that will attract one another and two that will repel one another.
The amino acid lysine has a positive charge, whereas aspartate has a negative charge. If these amino acids occur in a protein, they can attract one another and bend the protein chain so that they lie close together. On the other hand, two lysines, both with a positive charge, will repel one another, pushing the two parts of the protein chain apart where they occur. Similarly, two aspartates, each with a negative charge, will also repel one another.
The third type of interaction is called hydrogen bonding. Although hydrogen bonds are weaker than the bonds that hold the atoms together to make up the amino acids in the protein chain, hydrogen bonding nevertheless plays a very important role, not only in protein folding, but elsewhere in chemistry too, particularly in conferring on water its unique properties. Hydrogen bonding depends on partial positive and negative charges (much smaller than those mentioned above) which are present in some molecules. A hydrogen bond can occur between a hydrogen atom with a partial positive charge (by virtue of its attachment to an oxygen or a nitrogen atom) in one part of the molecule, and a different oxygen atom or nitrogen atom (which has a partial negative charge), elsewhere in the same molecule, or in another molecule. A hydrogen bond is normally represented by a dashed (or dotted) line, as follows:
Look back at Figure 4b and identify which of the hydrogen bonding types (i)-(iv) could occur in proteins.
All of these are possible. Figure 4b shows only two amino acids joined together, but a complete polypeptide molecule would contain C=O and N—H groups at regular intervals along the chain. So, type (i) could occur between an O—H group at the end of each protein chain, or an O—H group in the R group of an amino acid such as serine (see Table 5), and an O atom in any one of the C=O groups. Type (ii) could occur between the same O—H groups and a N atom in one of the N—H groups. Type (iii) could occur between the H from one of the N—H groups and an O atom from a C=O group elsewhere in the chain and type (iv) between an H from one N—H group and a N atom from another N—H group elsewhere. There will also be hydrogen bonding between some of the R groups of the amino acids making up the protein chain.
These hydrogen bonds hold parts of the protein together and they constitute another of the reasons the molecule adopts a particular shape.
Finally, the shape of a protein molecule can be stabilised by disulfide bridges which are standard bonds that form between two sulfur atoms in the R groups of the amino acid, cysteine (see Table 5). This type of bond can occur both between two cysteines in the same polypeptide chain (intra-chain bridge) and between cysteines in adjacent polypeptide chains (inter-chain bridge), holding together two polypeptide chains to form a single protein molecule. You can see both intra- and inter-chain disulfide bridges in the hormone insulin in Figure 8.
The amino acids are: phenylalanine (Phe), valine (Val), asparagine (Asn), glutamine (Gln), histidine (His), leucine (Leu) and cysteine (Cys).
(a) List the four interactions described above that determine the shape of a protein molecule, and briefly summarise the features of each one.
(b) Occasionally, due to a change (mutation) in the DNA code for a particular protein, a protein is synthesised with an incorrect amino acid at one position along the chain. Taking each of the four interactions in turn, consider whether a change in that single amino acid is likely to alter the shape and therefore disrupt the function of the protein in the body.
(a) The four interactions are:
Hydrophobic interactions. Those R groups that attract water molecules mostly lie on the outside of the folded protein; those that do not interact with water are clustered together on the inside of the folded chain.
Ionic interactions. Some amino acids have charged R groups, which attract oppositely charged R groups and repel those with like charges.
Hydrogen bonds. Depend on partial charges. They occur between H attached to O or N, and O or N elsewhere in the polypeptide chain or in a different chain.
Disulfide bridges. Occur between the sulfur atoms in the R groups of cysteine molecules in different parts of the same polypeptide chain, or in different chains.
(b) If the change in the amino acid was from one with a hydrophobic R group to one with a hydrophilic R group (or vice versa), then it could cause the protein chain to fold differently. Similarly, if the change in the amino acid produced a change in the charge of the R group, then this could affect the ionic interactions and could affect the folding. Since hydrogen bonding can occur between R groups, a change could affect those interactions too, and thus affect folding. Disulfide bridges occur only between cysteines, so if the change involved a cysteine, then the folding would be affected, whereas if not, the disulfide bridges would remain unchanged. (SP4.6.2 looks at a protein that is affected in a major way by a single amino acid change.)