Amino acids are linked by the peptide bonds in a protein. If the chain is long it is also referred to as polypeptide chain. Proteins and polypeptide are used as synonyms (Nelson & Cox, 2000)
Amino acids are linked in a linear sequence giving the primary structure. The linear sequence folds at some place due to the hydrogen bonding and forms disulphide bonds by cysteine residues resulting to the formation of secondary structures. Further folding of secondary proteins due to some forces like hydrogen bonds, hydrophobic interaction, weak van der Waals force gives a complex structure which is referred to as tertiary structure. The tertiary structures are referred to as 3-d structures of proteins. Looking at the molecular weight tertiary proteins are further divided into domains. Domains are characterized by some interesting features which I have mentioned some in the body. Structural and functional domains are modules of tertiary structures. (Lodiah et al, 2004). Now the overall protein structure aggregates the polypeptide subunits resulting in the formation of quaternary structure.
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These higher level of structure are convenient to classify proteins into two major groups; fibrous & globular proteins.
Proteins function is diverse, starting from mechanical support to carrier proteins to storage proteins to signaling proteins and their function mainly depends on the structure.
So the sequencing of amino acids in a polypeptide determines its structure and function.
Amino acid sequence specifies the shape of a protein. Out of 20 amino acids, 9 (Gly, Ala, Val, Leu, Ile, Met, Phe, Trp, & Pro) are hydrophobic as we can notice the hydrocarbon nature of the R groups with oxygen & nitrogen conspicuous by their absence. These tend to be interior of the molecule in a 3-d molecule. The remaining 11(Ser, Thr, Cys, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His) are hydrophilic, with R groups polar or charged at the pH values characteristic of cells. These amino acids lie on the surface of proteins (Becker et al, 2006)
Secondary structure consists of various spatial arrangements resulting from the folding of localized parts of a polypeptide chain. According to Campbell et al, 2005, both the oxygen & nitrogen atoms backbone are electronegative with partial negative charges. The weakly positive hydrogen atom attached to the nitrogen has an affinity for the oxygen atom of a nearby peptide bond.
It consists of
The alpha (Î±) helix,
The beta (Î²) sheet which on average 60% of the polypeptide exist as & the remainder of the molecule is in random coils & turns. The Î± helices & Î² sheets are the major internal supportive elements in proteins.
It is a delicate coil held together by hydrogen bonding (Campbell et al, 2005). The carbonyl oxygen atom of each peptide bond is hydrogen-bonded to the amide hydrogen atom of the amino acid four residues towards the C-terminus. The Î±-helix ranges from one to multiple stretches in globular proteins separated by non helical regions. It confers directionality on the helix because all the H-bond donors have the same orientation.
It consists of laterally packed Î² strands. In this structure two or more regions of the polypeptide chain lying side by side are connected by hydrogen bonds between parts of the parallel polypeptide backbones (Campbell et al, 2005). Hydrogen bonding between backbone atoms in adjacent Î²-strands, within either the same polypeptide chain or between different polypeptide chains, forms a Î²-sheet. Their planarity is pleated so they are also called a Î² pleated sheet (Lodish et al, 2004).
Besides above mentioned, turns are located on the surface of a protein, forming sharp bends that redirect the polypeptide backbone back towards the interior. These short, U-shaped secondary structures are stabilized by a hydrogen bond between their end residues.
Regular combinations of secondary structures called motifs or folds form the tertiary structure of a protein.
Overall folding of a polypeptide chain yields its tertiary structure.
Tertiary structure is the overall shape of a polypeptide resulting from interactions between the side chains (R groups) of the various amino acids. The overal 3-d arrangements of all atoms in all atoms in a proteins tertiary structure (Nelson & Cox, 2000).
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Hydrophobic interaction contributes to tertiary structure. As a polypeptide folds into its functional conformation, amino acids with hydrophobic (non polar) side chains usually end up in clusters at the core of the protein out of contact with water. As they are shielded inside van der Waals interactions help hold them together. The hydrogen bonds between polar side chains & ionic bonds between positive & negative charged side chains also stabilize tertiary structure, to some extent.
The stability of protein is further enhanced by covalent bonds called disulphide bridges. When two cysteine monomers, are brought together by the folding of the protein there results formation of disulphide bridges. The sulfur of one cysteine bonds to the sulfur of the second.
Fig. Formation of disulphide and hydrophobic interaction (Campbell, 2000)
Common folding patterns of protein tertiary structure are Î²-Î±-Î² folding unit. Î±-helices are formed when polypeptide chain is dominated by clusters of amino acids with Î±-helix preference. Î²-sheets are randomly scattered throughout the sequence. 'Breaker' amino acids interrupts the helix & results in a compact form. Pro, Gly, Ser, Asn, Asp, Thr are common amino acid breakers.
Patel, 2010 states "antiparallel beta sheet proteins form when the polypeptide sequence contains clusters of amino acids with beta sheet preference". Î±-helix are scattered randomly & with Î²-sheet strands & are interrupted by turns & breaker amino acids making them coil & turn.
Example, the structure of tirose phosphate isomerase consists of alternating Î²-strands & Î±-helix segments.
Figure: Tertiary structure of tirose phosphate isomerase.
Proteins fold Î²-Î±-Î² units, which lines Î²-sheets in parallel position. Both the sides of these sheets have non-polar amino acids. The parallel Î² sheets line the Î±-helices on one side. Besides Î±-helix appearing on one side, Î±-helices on both sides are also possible. These form folding called domains.
If the molecular weight of tertiary structure of proteins is larger than 15,000MW than it is divided into domains. Domain is the compactly folded region of polypeptide. Very often, characterization of domain is done by some interesting feature; an unusual abundance of a particular amino acid sequences common to many proteins or a peculiar secondary structure motif. Sometimes domains are defined in functional terms. For example a particular region or regions of a protein may be responsible for its catalytic activity (e.g., kinase domain). Structural & functional domains are modules of tertiary structure (Lodish et al, 2004).
Amino acid sequence determines tertiary structure
The experiment carried out by Christian Anfinsen in 1950s is the most important proof. It involved denaturation & renaturation of ribonuclease. Pure ribonuclease was completely denatured by using urea solution in presence of a reducing agent. The reducing agent cleaved the four disulphide bonds to yield eight Cys residues, & the urea disrupts the stability of hydrophobic interactions. This resulted denaturation & was accompanied by a complete loss of catalytic activity. On removal of urea & a reducing agent, renaturation took place in its correct tertiary structure, with full restoration of its catalytic activity (Nelson & Cox, 2000).
Nelson & Cox, 2000, state this experiment provided the first evidence that the amino acid sequence of a polypeptide chain contains all the information required to fold the chain into its native 3-d structure. The 3-d structure of ribose is due to the disulfide bonds formed by the cysteine residues and hydrophobic interactions of the amino acid sequence in a polypeptide chain. As shown in the diagram it was confirmed that the amino acid sequence in a polypeptide chain contains all the information required for protein folding into its native structure.
Aggregation of polypeptide chain form quaternary structures. This makes easier to categorize proteins into fibrous and globular proteins.
These are structural proteins, generally insoluble in water, consisting of long cable-like structures built entirely of either helical or sheet arrangements. The concentration of hydrophobic amino acids residues is high both, on the surface and the interior of the proteins (Nelson & Cox, 2000). This type of proteins consists of single type of secondary proteins (Wilson & Walker, 2005). Fibrous proteins constitute Î±-keratin, collagen & silk fibres. Î±-(Nelson & Cox, 2000) stated keratin are right handed Î±-helix. Î± keratin constitute wool, nails, claws, horns, hooves & outer layer of skin. The arrangement of proteins is, the parallel sheets coil together & form a strong one. Hardest alpha keratin has cysteine residue forming disulphide bond. Eg, Rhinoceros horn. Collagens are fibrous proteins present in connective tissue such as tendon, cartilage, the organic matrix of bones & cornea of eye. The sequencing of amino acid in collagen is a repeating tripeptides unit -Gly-X-Pro, where X-can be any amino acid residue.
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They are approximately spherical in shape, generally water soluble. It may contain a mixture of Î±-helices, Î²-pleated sheet & random structures. It includes enzymes, transport proteins, motor proteins, regulatory proteins & immuniglobins. Example myoglobin, its single polypeptide chain of 153 amino acids folds in 3-d structure. Its backbone consist a straight segment of Î±-helix interrupted by bonds and some are Î²-turns.
Functionally fibrous proteins provide mechanical support for cells & tissues (Patel, 2010). This includes proteins in skin, hair, nails (Bhagavan, 2002).
Globular proteins are in many forms.
Enzymes are biological catalysts, like enzymes involved in digestion or breaking down of toxins. They are catalysts for biological reactions. They work by using minimum amount of energy and in an efficient manner. In proteins it is the proteins 3-d shape adopted by the enzyme protein that makes it suitable for its specific function. Enzymes have binding site where ligands can fit, the binding sites are called as active site & the ligand as subtrate.
Enzymes are made up of many proteins. Each protein has a unique 3-d structure. It has unique amino acid sequence and it plays a fundamental role in determining the 3-d structure of protein and finally an enzyme. If the ligands 3-d structure is same as that of the active site of the enzyme than catalysis takes place otherwise it fails in catalyzing the reaction.
Figure : Enzyme action: catalysing a reaction, (a) The substrate is the right shape to fit into the active site; (b) it bonds there, causing it to distort and thus lowering the energy barrier; (c) this allows it to break down into products, which then leave the active site
Transport proteins transport small molecules or ions from one place to another, e.g., haemoglobin carries oxygen in blood. Myoglobin binds oxygen in muscles of mammals. It almost resembles haemoglobin. The backbone of myoglobin is made up of straight segments of Î±-helix interrupted by bends with some Î²-turns. The molecules are so compact that its interior has only four molecules of water and is hydrophobic.
Some proteins carry signals between or within cells like hormones, e.g., insulin controls blood sugar level. Some act as receptor proteins detecting signals & transmitting them within cells like rhodospin detecting light in the eye. Motor proteins generate movement in cells, e.g., myosin is involved in muscle movement.
The experiment performed by Christian Anfisen shows that the structure determines the function of proteins. Denaturation of ribonuclease is accompanied by a complete loss of function when the urea and Î²-mercaptoethanol is removed. Denatured ribonuclease refolds to correct tertiary structure and regain its full catalytic activity. This reveals that a particular structure determines its function.
In conclusion, the amino acid sequence in primary structure determines the 3-d structure of proteins because of the forces responsible for stabilizing the 3-d structure like hydrogen bonding; hydrophobic interactions make up particular polypeptide.
Similarily the structures determine its function. Different amino acid sequences have different structures and have different functions. Example, haemoglobin carries oxygen in the blood and myoglobin carries oxygen in muscles of mammals.
So I conclude, the primary sequence of amino acid determines its 3-d shape and due to its shape its function is also specified.