The primary structure of a segment of a polypeptide chain or of a protein is the amino-acid sequence of the polypeptide chain(s), without regard to spatial arrangement (apart from configuration at the alpha-carbon atom). This definition does not include the positions of disulphide bonds, and is, therefore, not identical with "covalent structure" (IUPAC-IUB, 1970). The commonly occurring amino acids are of 20 different kinds which contain the same dipolar ion group H3N+.CH.COO-. They all have in common a central carbon atom to which are attached a hydrogen atom, an amino group (NH2) and a carboxyl group (COOH). The central carbon atom is called the Calpha-atom and is a chiral centre. All amino acids found in proteins encoded by the genome have the L-configuration at this chiral centre.
This configuration can be remembered as the CORN law. Imagine looking along the H-Calpha bond with the H atom closest to you.
When read clockwise, the groups attached to the Calpha spell the word CORN (Richardson, 1981). There are 20 side chains found in proteins encoded by the genetic machinery of the cell. The side chains confer important properties on a protein such as the ability to bind ligands and catalyse biochemical reactions. They also direct the folding of the nascent polypeptide and stabilise its final conformation. In molecular graphics, atoms can be represented in different ways. For expedience, molecules are often displayed only as lines or vectors between the atoms bonded together covalently. An elegant representation is the ball-and-stick type in which atoms are drawn as coloured spheres and their bonds as rod-like connections. Another useful display is the space-filling representation in which a surface is drawn around the atoms to indicate their van der Waals radii. This surface can be drawn as a series of dots or as a solid entity (Lesk, 1991). Amino acids in proteins(or polypeptides) are joined together by peptide bonds. The sequence of R-groups along the chain is called the primary structure.
The Peptide bond
Pauling et al. (1951) analysed the geometry and dimensions of the peptide bonds in the crystal structures of molecules containing either one or a few peptide bonds. Their results are summarised in the diagram below where the consensus bond lengths are shown in Angstrom units. Bond angles in degrees are also shown for the peptide N and C atoms. It should be noted that the C-N bond length of the peptide is 10% shorter than that found in usual C-N amine bonds (Schulz and Schirmer, 1990; Creighton, 1993).
This is because the peptide bond has some double bond character (40%) due to resonance which occurs with amides. The two canonical structures are:
As a consequence of this resonance all peptide bonds in protein structures are found to be almost planar, i.e. atoms Calpha(i), C(i), O(i), N(i+1) and Calpha(i+1) are approximately co-planar. This rigidity of the peptide bond reduces the degrees of freedom of the polypeptide during folding. The peptide bond nearly always has the trans configuration since it is more favourable than cis, which is sometimes found to occur with proline (Pro) residues (Schulz and Schirmer, 1990).
As can be seen from the previous page, steric hindrance between the functional groups attached to the Calpha atoms will be greater in the cis configuration. However, for proline residues, the cyclic nature of the side chain means that both cis and trans configurations have more equivalent energies. Thus proline is found in the cis configuration more frequently than the other amino acids.
Properties of amino acids
The sequence and properties of side chains determine all that is unique about a particular protein, including its biological function and its specific three-dimensional structure. Histidine (His) is the only side chain that titrates near physiological pH, making it especially useful for enzymatic reactions.
Lysine (Lys) and arginine (Arg) are normally positively charged and aspartate (Asp) and glutamate (Glu) are negatively charged. These charges are very seldom buried in protein interiors except when they are serving some special purpose, as in the activity and activation of chymotrypsin (Blow et al., 1969; Wright, 1973).
Asparagine (Asn) and glutamine (Gln) have interesting hydrogen-bonding properties, since they resemble the backbone peptides. The hydrophobic residues provide a very strong driving force for folding, through the indirect effect of their ceasing to disrupt the water structure once they are buried (Kauzmann, 1959). They also, however, affect the structure in a highly specific manner because their varied sizes and shapes fit together in very efficient packing (Lee and Richards, 1971).
Proline has stronger stereochemical constraints than any other residue, with only one instead of two variable backbone angles, and it lacks the normal backbone NH for hydrogen bonding. It is both disruptive to regular secondary structure and also good at forming turns in the polypeptide chain, so that in spite of its hydrophobicity it is usually found at the edge of the protein (Richardson, 1981).
Glycine (Gly) has three different unique capabilities. As the smallest side group (only a hydrogen), it is often found where main chains approach each other very closely. In addition Gly can assume conformations normally restricted by close contacts of the beta-carbon and finally it is more flexible than other residues, thus contributing to parts of the backbone that need to move or hinge (Richardson, 1981).
Serine (Ser) and threonine (Thr) carry aliphatic hydroxyl groups capable of forming hydrogen bonds with suitable donor or acceptor groups, such as the imino nitrogen or the carbonyl oxygen of the main polypeptide chain. Serine reacts with phosphate by an ester bond, forms part of the catalytic site of many hydrolytic enzymes (Dickerson and Geis, 1969) and contributes to the lining of ion channels. Serine, threonine, and asparagine are also the binding sites of carbohydrates that are attached to the surface of many proteins. Carbohydrates bound to serine and threonine form O-glycosidic bonds and those linked to asparagine form N-glycosidic bonds (Perutz, 1992).
Cysteine (Cys) carries the highly reactive sulphydryl group. This does not ionise at physiological pH nor form hydrogen bonds of significant strength, but two cysteines placed some distance apart along a polypeptide chain, or forming part of different chains, can be joined by oxidation to form the disulphide bridge of cystine which plays an important part in stabilizing protein structures. Disulphide bonds increase the conformational stability mainly by constraining the unfolded conformations of the protein and thereby decreasing their conformational entropy (Pace, 1990). Cysteines also bind zinc, copper, and iron ions. The sulphur atom in methionine is unreactive and generally serves no function other than imposing a special configuration on the aliphatic sidechain, but in cytochrome c it forms the link between the protein and the heme iron (Olson, 1992).
Protein structure determination
In terms of the accuracy of protein structure determinations, all of the bond lengths are invariant. Bond angles are also essentially invariant, except perhaps for , the backbone N-Calpha-C angle. The alpha-carbon is tetrahedral, which would give 110°, but there are indications from accurately refined protein structures (Deisenhofer and Steigemann, 1975; Watenpaugh et al., 1979) that can sometimes stretch to larger values in order to accommodate other strains in the structure. The dihedral angle at the peptide is very close to 180° (producing a trans, planar peptide with the neighbouring alpha-carbons and the N, H, C, and O between them all lying in one plane). The remaining dihedral angles are the source of essentially all the interesting variability in protein conformation. The backbone dihedral angles are and in sequence order on either side of the alpha-carbon, so that is the dihedral angle around the N-Calpha bond and around the Calpha-C bond. The side chain dihedral angles are 1, 2, etc. An extremely useful device for studying protein conformation is the Ramachandran plot (Ramachandran et al., 1963) which plots and . The values of and that are possible are constrained geometrically due to steric clashes between non-neighboring atoms. The permitted values of and are indicated on a two-dimensional map of the - plane (Branden and Tooze, 1991).
Secondary Structure
The secondary structure of a segment of polypeptide chain is the local spatial arrangement of its main-chain atoms without regard to the conformation of its side chains or to its relationship with other segments (IUPAC-IUB, 1970). There are three common secondary structures in proteins, namely alpha helices, beta sheets and turns. That which cannot be classified as one of the standard three classes is usually grouped into a category called "other" or "random coil". This last designation is unfortunate as no portion of protein three dimensional structure is truly random and it is not a coil either. Regular secondary structure conformations in segments of a polypeptide chain occur when all the bond angles in that polypeptide segment are equal to each other, and all the bond angles are equal. The rotational angles for and bonds for common regular secondary structures are shown in the table below.
John Cowdery Kendrew was born on 24th March, 1917, in Oxford. His father, Wilfrid George Kendrew, was Reader in Climatology in the University of Oxford; his mother, Evelyn May Graham (Sandberg) Kendrew, was an art historian, for many years resident in Florence, Italy, where she published works on the Italian Primitives under the nom de plume Evelyn Sandberg Vavals.
He was educated at the Dragon School, Oxford (1923-1930) and Clifton College, Bristol (1930-1936), and went to Trinity College, Cambridge in 1936 as a Major Scholar. He graduated in Chemistry in 1939, and spent the first few months of the war doing research on reaction kinetics in the Department of Physical Chemistry at Cambridge under the supervision of Dr. E.A. Moelwyn-Hughes. He then became a member of the Air Ministry Research Establishment (later Telecommunication Research Establishment) and worked on radar. In 1940 he joined the staff of Sir Robert Watson-Watt (Scientific Adviser to the Air Ministry) and for the rest of the war was engaged in operational research at Royal Air Force headquarters, successively in Coastal Command, Middle East, and South East Asia (where he was Scientific Adviser to the Allied Air Commander-in-Chief); he held the honorary rank of Wing Commander R.A.F.
During the war years his interests became more biological, and largely owing to the influence of J.D. Bernal and L. Pauling he decided to work on the structure of proteins. He returned to Cambridge in 1946 and, in the Cavendish Laboratory, began a collaboration with Max Perutz, under the direction of Sir Lawrence Bragg. He took his Ph.D. degree in 1949 and his Sc.D. in I962. He and Perutz were the first two members of the Medical Research Council Unit at the Cavendish Laboratory, which has now achieved separate existence as the Medical Research Council Laboratory of Molecular Biology; he was Deputy Director of the former, and is now Deputy Chairman of the latter, and Director of its Division of Structural Studies.
He became a Fellow of Peterhouse in 1947, Reader at the Davy-Faraday Laboratory of the Royal Institution in London in 1954, Fellow of the Royal Society in 1960, and an honorary member of the American Society of Biological Chemists in 1962. Since 1960 he has been (part-time) Deputy to the Chief Scientific Adviser, Ministry of Defence. He is Founder and Editor-in-Chief of the Journal of Molecular Biology, and Honorary Secretary of the British Biophysical Society. In 1962, he was made Companion of the British Empire.
His research has been in the field of protein structure, and has mostly centred on the X-ray analysis of myoglobin. This project culminated in the production of a three-dimensional model of myoglobin at 6? resolution in 1957, and an almost complete structure in 1960. Kendrew is unmarried. His recreations are music, history of art (following his mother's footsteps particularly Italian art), and travelling in Italy.
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