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A protein is a polymer of amino acids in which carbon atoms and peptide groups alternate to form a linear polypeptide chain. When many amino acids are joined, the product form is called a polypeptide and this gives the protein structure. In order to understand the structure and function of a protein in detail, it is important for us to know the kinds of amino acids present in the protein and their order. Each protein molecule has a unique 3D structure that will be determined by the amino acid sequence of that protein. Not only that, it also provide information that is necessary to understand the effects of mutation, the mechanism of enzyme-catalyzed reaction, and the chemical synthesis of species-specific peptides. (Bhagavan, 2002).
The great diversity of protein structure helps to carry out the different functions required by the cells. The functions are most diverse and some proteins just speed up the rate of reaction like enzymes, and while others carry out structural functions by stabilizing a living cell's shapes. So, in order to understand the manner in which proteins manage to carryout such diverse functions, it is important to know the individual amino acids contribute a structural feature to a protein. The linear sequence of amino acids will twist, fold and aggregate, in which each of structure will contribute to a protein's functions. Normally the protein chain gets folded into a unique shape that is stabilized by the interaction called the noncovalent interaction between the regions in the linear sequence of the amino acids. This organization of the protein that is , its shape in the 3D structure is a key to understand its functions. A protein functions efficiently only when it is in the correct 3D structure. We know that the protein function is derived from the 3D structure, and 3D structure is specified by amino acids sequence. The structures of proteins are operated at four levels of organization, starting with their monomeric building blocks, amino acids. (Lodish et al, 2004)
3D Structure of proteins
In protein, the alpha carbonyl group of one amino acids is joined to the alpha amine group of other amino acids by peptide bonds. Different levels of protein structure are commonly identified and define which ultimately determines the final 3D structure of the proteins.
In Primary structure, the linear arrangement or sequence of amino acid residues, and usually, it is dictated by the base sequence of the corresponding gene. The primary sequence of amino acids is a key point to dictate the folding patterns and final 3D structure of the proteins. (Freifelder et al,1998).
In Secondary structure, the structure of protein consists of the various spatial arrangements resulting from the folding of localized part of a polypeptides chain. The linear sequence of amino acids (primary structure) folds into helices or sheets .Depending on the sequence, a single polypeptide chain may exhibit multiple types of secondary structure, and chain folds because of following tendencies;
*Hydrogen bonds form between carbonyl oxygen of one peptide and the hydrogen attached to nitrogen atom in another peptide bond
*The sulfhydryl group of the amino acids cysteine to form a covalent s-s (disulphide) bond.
*Ionic bonds between the oppositely charged groups in acidic and basic amino acids
On the other hand, in the absence of any interaction between the different part of
Polypeptide chain, a random coils would be the conformation. (Freifeider, 1998)
According to Pauling and Corey (1950), the most common secondary structure is identified as Î± helix and Î² sheet. (Lodish et al, 2008)
*In alpha helix, the polypeptide chains are in a helical path which is stabilized by the H-bonding between the hydrogen atom which attached to electronegative nitrogen of a peptide bond and electronegative carbonyl oxygen atom of the fourth amino acids which is on the terminal side of that peptide bond. The stable arrangement of amino acids in the alpha helix holds the backbone in a rod like cylinder from which the side chain point outward. We also know that the hydrophobic or hydrophilic quality of helix is determined by the side chains because the polar group forms the H-bonds in the helix. (Lodish et al, 2004)
*The Î² sheet is laterally packed strand and the backbone of the extended polypeptide chain is arranged in zigzag manner. In this arrangement, the H- bond is form between the adjacent side of the polypeptide chain, within either the same polypeptide chain or between different polypeptide chains forming a Î² sheet. Like Î± helices, Î² sheet are oriented by the peptide bond, therefore, adjacent Î² sheets can be oriented in same (parallel) or opposite (ant parallel) direction with respect to each other but they differ in direction of R group and strength of H-bonds.(Nelson et al,2000)
. In secondary structure are stabilized and folded by the hydrogen bond but in tertiary structure involves the long range aspects of amino acids sequence and hydrophobic interaction plays a key role in this structure. Tertiary structure is stabilized by hydrophobic interactions between the polar side chains and peptide chains. The folding of 3D structure of polypeptide chain is such that the non polar are away from the aqueous environment and the polar and ionized residues are on the outer surface of the molecules. (Lodish et al, 2004 & Wilson et al, 2005). The stabilizing forces hold the elements secondary structure such as Î± helix, Î² sheet, turns and random coils compactly together. The most prevalent interactions responsible for tertiary structure are the following;
1) The Hydrophobic clusters between hydrophobic side chains of non-polar residues
2) The ionic interaction between the oppositely charge groups (Freifelder, et al, 1998)
3) Tertiary structure is maintained by disulfide bonds. Disulfide bonds are formed between the side chain of cysteine by oxidation of two thiol groups (SH) to form a disulfide(S-S). (Wilson, &Walker, 2005)
Fig. Disulfide bond.
Figure; The three dimensional structure of a protein. (Camphell, n.d)
Amino acid sequence specifies 3D structure
The experiments carried out by Christian Anfinsen (1950) and their colleagues on ribonuclease, an enzyme that hydrolyze RNA first showed the importance of amino acid sequence in the determination of native conformation. (Nelson et al,2000).When the native conformation is treated with 8M urea in the presence of reducing agent Î² mercaptoethanol leads to complete unfolding of the ribonuclease molecules which gives a random coiled polypeptide chain devoid of enzymatic activity(become functionless), or on the other words, ribonuclease was denatured by this treatment. In this process the four disulfide bonds formed by eight cystine were cleaved by Î²-mercaptoethanol, converting them into eight cysteine.But when the urea and Î²-mercaptoethanol was removed slowly from the ribonuclease by dialysis, the enzymatic activity(function) of ribonuclease gradually returned or regained, which indicates that even after unfolding, ribonucleases still fold back into its catalytically active tertiary structure. So, the eight cystine residue are reoxidized by atmospheric oxygen to regained four disulfide bonds which shown in the figure. This four cysteine bonds were same as that of native conformation. Detailed studies showed that nearly all of the original activity was regained if the sulfhydryls were oxidized. So, that on a random basis eight cysteine residues in a single polypeptide chain can form 105 sets of four different disulfide pairs but only one is enzymatically active and 104 wrong pairing have been recognized and termed as scramble ribonuclease. The experiment shows that the amino acids sequence of ribonuclease accurately and precisely determines the arrangement of -SH groups to yield the correct disulfide cross links. Not only that this experiment on renaturation of other globular proteins, established that the amino acids sequence specifies the distinctive tertiary structure of globular protein. The information needed to specify the complex three dimensional structure of ribonuclease is contained in its amino acids sequences. (Lehninger, 1995, &Styer, 1981)
Fig. Reduction and Denaturation of Rubonuclease
Fig. Reestablishing correct disulfide pairing (Stryer, 2002)
The diversity of proteins structure and determination of function from its structure
The proteins are classified into two major groups;
1) Fibrous proteins
They are structural proteins and are adapted for structure functions, in which polypeptide Chains arranged either helical or sheets. In this type, it consists of single type of secondary structure. Generally all fibrous proteins are insoluble in water, and there is a high concentration of hydrophobic amino acids residues both in the interior and on the surface of proteins.
(Nelson et al,2000).It includes the collagen, Î±-keratin, silk fibroins The structure is simple and in repeating manner , and have structure such as right-handed Î± helix, the anti parallel and parallel Î²-pleat sheets.(Conn et al,1976)
The Î±-keratin constitutes the protein of hair, wool, nails, claws, horns, hooves, and other layer of skins. According to Francis Cricks and Linnus Pauling (1950) suggested that helices of keratin are arranged in coiled coil. And also two strands of Î±-keratins are arranged in parallel and twist each other to form a super twisted coiled coil. This twisting makes the strength of overall structure, just as strands are twisted to make a strong rope. Pair of these helices is intertwined in a left- handed side to form two chain coiled coils. These then combined in higher structure called protofilament and profibril.So, the intertwining of two helical polypeptide is an example of quaternary structure and are quite complex. The longest and hardest Î±-keratin, such as rhinoceros horn is the residues of cysteine involved in disulfide bond. This protein functions as mechanical support for cells and tissues, and also called as Structural protein. (Nelson et al, 2000)
In this type, the polypeptide chains folded into a spherical or globular shape and have a fully extended conformation. This compact folding of 3D structure provides the structural diversity which is necessary for protein to carry out the functions. This protein includes enzymes, transport proteins, motor proteins, regulatory proteins, immunoglobins, and other proteins. In general, all the polar R groups of the amino acids are located at the outer surface and are hydrated, on other hand, nearly all non-polar R groups in the interior of the molecules. (Nelson et al, 2000).
It is relatively small globular proteins containing a single polypeptide chainof 153 amino acids residues.It also contain iron-prophyrin, or heme group which is identical with that of hemoglobin. In myoglobin the polypeptide chain is folded in 3dimensions-its tertiary structure. The backbone of myoglobin molecule is made up of straight segments of Î±-helix interrupted by bends, some of which are Î² turns. The longest Î±-helix has 23 amino acids and the shortest only 7 and all are right-handed. Moreover, about 70%of the amino acids are in the Î±-helix. The myoglobin molecules are so compact that its interior has only four molecules of water and this dense hydrophobic core is typical of globular protein. Myoglobin is a relatively simple oxygen binding protein found in almost all mammals in muscles and particularly in deep sea animals such as seals and whales that must store enough oxygen for prolong stay in the water. It is a transport protein and serves as reserve supply of oxygen and facilitates the movement of oxygen within muscles. (Lehninger, 1995)
Fig.Myoglobin (Seneff, 2003)
It is also a globular protein and is signaling protein which control blood sugar level. Insulin consist of two chain-an A chain with 21 residues and a B chain with a 30 residues which are covalently joined by two disulfide bonds. It has a compact 3D structure, and only the amino and carbonyl termini of the B-chain are extended away from the rest of the protein. The chain is located between these extended arms of B chain. Insulin is stabilized by several links and by hydro den bonds between A and B chain, in addition to its disulfide bonds. The structure of insulin plays a vital role lowering the level of glucose in blood (hypoglycemic effects). It is a polypeptide hormone that increases the rate of synthesis of glycogen, fatty acids, and protein. (Styer, 1981)
It is motor protein and has six subunits; two heavy chains and four light chains. The heavy chain plays an important role in overall structure, and they are arranged in such a way that at their carbonyl termini, as extended Î±-helices and are wounded each other in a fibrous similar to Î±-keratin. At the amino termini, heavy chain has a large globular domain containing site where ATP is hydrolyzed. Both the heavy polypeptides chains are folded into globular structure to form a head. This head contains four smaller or light chains associated with two heads of heavy chains. So, when myosin is treated with enzyme protease trypsin, the fibrous tail is shed off, separating protein into light and heavy meromyosin, and myosin head is further liberated from heavy meromyosin by papin.This sub fragment makes muscle contraction possible and great movement in muscles.(Nelson et al,2000).
Fig. Myosin (Diwan, 2007)
Structure determine the function for protein
We know that 3D structure of protein plays an important role in protein function.Protien will function invariably depend on interaction with other molecules. Loss of structure is loss of function. A loss of three dimensional structure is sufficient to cause loss of function is called denaturation,and certain globular protein may denatured by heat ,which affects the weak interaction in a protein, extreme of PH,certain organic solvent such as detergents will regain their native structure and their biological functions by the process called renaturation. As discussed earlier, according to the experiment done by Christian Anfinsen (1950),denaturation of ribonuclease is accompanied by a complete loss of function and when the urea and Î²- mercaptoethanol is removed, denatured ribonuclease refolds into correct tertiary structure and regain its full catalytic activity and the functions. This shows that structure determines the function of proteins. (Nelson et al, 2000)