Educational guide
Peptide Bond - an overview
Chapters and Articles You might find these chapters and articles relevant to this topic. 1.9.4 Linkage between Amino Acids—The Peptide Bond Amino acids are linked together by peptide bonds ( alpha peptide bonds ), which are simply amide linkages between the NH
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Chapters and Articles
You might find these chapters and articles relevant to this topic.
1.9.4 Linkage between Amino Acids—The Peptide Bond
Amino acids are linked together by peptide bonds (alpha peptide bonds), which are simply amide linkages between the NH2 and COOH groups of neighboring amino acids. The peptide bond has unique characteristics, which contribute to the overall structure of proteins. The peptide bond has a partial double-bond character. Thus, it is rigid and planar and not free to rotate. The plane on which it lies is called the amide plane. Peptide bonds are generally trans bonds—that is, the carbonyl oxygen and amide hydrogen are in trans position (Figure 1.6E). The CαC bonds are not rigid and they can freely rotate, being only limited by the size and character of the R groups. In lysine, the ε-amino group (Figure 1.6D) also participates in the formation of a peptide bond, which is called an isopeptide bond because it does not involve the usual α-amino group.
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Peptide Bond
Peptide bonds have a planar, trans, configuration and undergo very little rotation or twisting around the amide bond that links the α-amino nitrogen of one amino acid to the carbonyl carbon of the next (Figure 4-1). This effect is due to amido–imido tautomerization. The partial double-bond character of the N—C bond in the transition state probably best represents what exists in nature. Electrons are shared by the nitrogen and oxygen atoms, and the N—C and C—O bonds are both (roughly) “one-and-one-half” bonds (intermediate between single and double). The short carbonyl carbon–nitrogen bond length, 0.132 nm (the usual carbon–nitrogen single bond length is 0.147 nm), is consistent with the partial double-bond character of the peptide linkage. The planarity and rigidity of the peptide bond are accounted for by the fact that free rotation cannot occur around double bonds.
Figure 4-1. Geometry of a peptide (amide) linkage.
For the peptide bond, bond angles and bond lengths indicate that carbon–nitrogen bonds have a significant amount of double-bond character, and that the C, O, N, and H atoms all lie in the same plane. The φ and ψ refer to rotations about the single bonds connecting the α-carbon with the α-nitrogen and the α-carbonyl carbon, respectively.
The bonds on either side of the α-carbon (i.e., between the α-carbon and the nitrogen, and between the α-carbon and the carbonyl carbon) are strictly single bonds. Rotation is possible around these single bonds. The designation for the angle of rotation of the α-carbon–nitrogen bond is φ, whereas that of the α-carbon–carbonyl carbon bond is ψ. Although theoretically an infinite number of φ and ψ angles are possible around single bonds, only a limited number of φ and ψ angles are actually possible in proteins. A polypeptide has specific φ and ψ values for each residue that determines its conformation.
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8.2 Peptide Bond, Peptide Plane, Bond Rotation, Dihedral Angles, and Ramachandran Plot
Amino acids are linked together by peptide bonds. Peptide bonds are amide linkages between the NH2 and COOH groups of neighboring amino acids. The peptide bond (CN) has a partial double-bond character. Thus, it is rigid and planar and not free to rotate. The plane on which it lies is called the peptide plane or amide plane. Peptide bonds are trans bonds—that is, the carbonyl oxygen and amide hydrogen are in trans position. However, the NCα and CαC bonds are not rigid and they can freely rotate, being only limited by the size and character of the R-groups. The angle of rotation (also called torsion angle or dihedral angle) around the NCα bond is called phi (φ) and that around the CαC bond is called psi (ψ) (Figure 8.1A). These two angles largely determine the 3D shape of the polypeptide backbone of the protein.
Figure 8.1. Peptide bond, peptide plane, and the Ramachandran plot.
(A) Peptide bond, peptide plane, phi and psi angles, and bond rotation involving two amino acids. The NCα and CαC bonds are not rigid and can freely rotate, being only limited by the size and character of the R-groups. (B) Diagram of a typical Ramachandran plot (φ/ψ plot). The regions marked “Core” correspond to conformations that do not have any steric hindrance. The yellow areas labeled “Allowed” correspond to conformations that could be possible if the atoms could come a little closer together. The white areas represent conformations that are sterically unfavorable (see text). (C) In computing a Ramachandran plot, atoms are treated as hard spheres whose dimensions correspond to their van der Waals radii. The van der Waals radius and covalent radius are depicted for comparison.
Although φ and ψ are less restricted in terms of rotation, the bulkiness of R-groups of the amino acids tends to impose some restrictions on the rotation through steric hindrance. This makes certain combinations of φ and ψ preferred. The φ/ψ plot of the amino acid residues in a peptide is called the Ramachandran plot. It involves plotting the φ values on the x-axis and the ψ values on the y-axis to predict the possible conformation of the peptide. The angle spectrum in each axis is from −180° to +180°. In computing a Ramachandran plot, atoms are treated as hard spheres whose dimensions correspond to their van der Waals radii. Any angle that results in the collision of the spheres is regarded as sterically unfavorable; hence, such conformations are also sterically not allowed. Figure 8.1B shows a simplified diagram of a Ramachandran plot. The regions marked “Core” correspond to conformations that do not have any steric hindrance. The yellow areas labeled “Allowed” correspond to conformations that could be possible if slightly shorter van der Waals radii are used in the calculation. In other words, if the atoms could come a little closer together, then these conformations would be possible. The white areas represent conformations that are sterically unfavorable. The van der Waals radius and covalent radius are depicted in Figure 8.1C. The residues with a less bulky side chain or no side chain, such as glycine (no side chain), can have many possible combinations of φ and ψ (e.g. in a polyglycine backbone) resulting in a larger allowable area on the plot in all four quadrants, whereas residues with bulky side chains, such as proline or phenylalanine, have fewer possible combinations of φ and ψ, hence a smaller allowable area on the plot.
The φ and ψ angles for each residue in a helical structure are very similar, and that is what confers regularity to the helical structure. Positive angles correspond to clockwise rotation and negative angles correspond to anticlockwise rotation. The ideal values of φ/ψ were determined to be as follows: right-handed α-helix −57°/−47°; left-handed α-helix +57°/+47°; right-handed 310 helix −74°/−4°; right-handed π-helix −57°/−70°; parallel β-sheet (uncommon) −119°/+113°; antiparallel β-sheet (common) −139°/+135°. The actual values differ somewhat from these idealized values. Recent experimental data have demonstrated that both φ and ψ can undergo large rotations, which are usually coupled. See Hovmöller, et al.6 for more details on experimental determination of main-chain conformations in 1042 protein subunits.
Online tools are available from several sources for the analysis of Ramachandran plots of proteins. One such tool is available at the Uppsala Ramachandran Server (http://eds.bmc.uu.se/ramachan.html). This service is based on the Moleman2 program.7
URL: https://www.sciencedirect.com/science/article/pii/B9780124104716000086
1.1.2 Formation of peptide bonds
The carboxyl group of one amino acid interacts with the amino group of another to form a peptide bond by the elimination of water (Figure 1.3). Amino acids are joined end-to-end during protein synthesis by the formation of such peptide bonds. The peptide bond (CN) has a partial double-bond character due to resonance, and hence there is no rotation about the peptide bond. In Figure 1.3, the peptide is represented as a planar unit with the CO and NH groups positioning in opposite directions in the plane. This is called trans-peptide. There is another form, cis-peptide in which the CO and NH groups point in the same direction. To avoid steric hindrance, the trans form is frequently presented in protein structures for all amino acids except Pro, which has both trans and cis forms. The cis prolines are found in bends of the polypeptide chains.
Figure 1.3. Formation of a peptide bond by the elimination of a water molecule.
A protein chain is formed by several amino acids in which the amino group of the first amino acid and the carboxyl group of the last amino acid remain intact, and the chain is said to extend from the amino (N) to the carboxyl (C) terminus. This chain of amino acids is called a polypeptide chain, main chain, or backbone. Amino acids in a polypeptide chain lack a hydrogen atom at the amino terminal and an OH group at the carboxyl terminal (except at the ends), and hence amino acids are also called amino acid residues (simply residues). Nature selects the combination of amino acid residues to form polypeptide chains for their function, similar to the combination of alphabets to form meaningful words and sentences. These polypeptide chains that have specific functions are called proteins.
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Peptide Bond
Peptide bonds have a planar trans configuration and undergo very little rotation or twisting around the amide bond that links the α-amino nitrogen of one amino acid to the carbonyl carbon of the next amino acid (Figure 4.2). This effect is due to amido–imido tautomerization. The partial double bond character of the NC bond in the transition state probably best represents what exists in nature. Electrons are shared by the nitrogen and oxygen atoms, and the NC and CO bonds are both (roughly) “one-and-one-half” bonds (intermediate between single and double). The short carbonyl carbon–nitrogen bond length, 0.132 nm (the usual carbon–nitrogen single bond length is 0.147 nm), is consistent with the partial double-bond character of the peptide linkage. The planarity and rigidity of the peptide bond are accounted for by the fact that free rotation cannot occur around double bonds.
Figure 4.2. Geometry of a peptide (amide) linkage.
Whereas most peptide bonds exist in the trans configuration to keep the side chains (R-groups) as far apart as possible, the peptide bond that involves the NH group of the rigid pyrrolidone ring of proline can occur in both trans and cis arrangements (Figure 4.3). However, X-ray data suggest that the trans form occurs more frequently in proteins than does the cis form. It has been further postulated that some proline residues (known as “permissive” proline residues) can exist in either the cis or trans configuration. For example, of the four proline residues of ribonuclease A, at least two are thought to be in the trans configuration in order to form a native structure, whereas one or both of the other residues may be accommodated in either the cis or trans configuration.
Figure 4.3. The trans and cis configurations of peptide bonds involving proline.
The bonds on either side of the α-carbon (i.e., between the α-carbon and the nitrogen, and between the α-carbon and the carbonyl carbon) are strictly single bonds. Rotation is possible around these single bonds. The designation for the angle of rotation of the α-carbon-nitrogen bond is Φ, whereas that of the α-carbon-carbonyl carbon bond is ψ. Although theoretically an infinite number of Φ and ψ angles are possible around single bonds, only a limited number of Φ and ψ angles are actually possible in proteins. A polypeptide has specific Φ and ψ values for each residue that determines its conformation.
URL: https://www.sciencedirect.com/science/article/pii/B978012416687500004X
Peptide oligomerization model for membrane-associated FP23 from the gp41 enveloping protein of HIV-1 for parallel (A) and antiparallel (B) strand arrangement. Structural studies have indicated a β-sheet structure including residues 5–16 (grey). Interstrand hydrogen bonding was probed by intermolecular 13C{15N} REDOR measurements. Peptide segments drawn in close proximity indicate REDOR dephasing in agreement with interresidue hydrogen bonding, for residues shown in the white box in the parallel arrangement (A) no REDOR dephasing, i.e. no intermolecular hydrogen bonds have been found.
URL: https://www.sciencedirect.com/science/article/pii/S0079656505000026
8.2 Protein structure
Proteins are polymeric biological macromolecules formed by the condensation of amino acids. The covalent bond between two successive amino acid residues in a protein is called the peptide bond. Hence, what makes each protein unique is the sequential order of the amino acid residues, which can be compared, for instance, to the succession of rosary beads (Fig. 8.1). Because the peptide bond links the carboxyl group of one amino acid to the amino group of the next one, the peptide chain is sequentially oriented. The amino group NH3+ of the first amino acid of the chain is not engaged in a peptide bond. Thus, this amino acid, numbered 1 in the sequence, defines the N-terminus of the peptide chain. At the other extremity of the chain, the carboxyl group of the last amino acid is also free and it logically defines the C-terminus.
Figure 8.1. The different levels of protein structure.
The primary structure (I) is the amino acid sequence. The sequence is numbered from the N-terminus to the C-terminus of the chain. Amino acid residues are the building blocks linked by a unique type of linkage, the peptide bond. Hence, what makes a protein unique is its amino acid sequence. The side chains of amino acid residues are represented as colored geometric symbols. The secondary structure (II) is formed by a local folding of the peptide chain into a highly regular segment (e.g., a helix). Two successive helices separated by a short linker are represented. To improve clarity, the amino acid side chains are not shown. The tertiary structure (III) corresponds to the spatial (3D) structure of the protein. Finally, the quaternary structure (IV) refers to multi-subunit proteins generally interacting through noncovalent bonds.
Students should realize how practical this situation is to locate any amino acid residue of a protein, just by its number in the sequence. Proteins can be schematized by drawing a simple line, generally oriented with the N-terminus on the left and the C-terminus on the right. If we ask for amino acid 39 of α-synuclein, an amyloid protein with 140 amino acid residues, we can immediately spot it without any ambiguity. The amino acid sequence of a protein is referred to as the primary structure. It is the first level of protein structure, directly translated from the mRNA by the genetic code. Schematically it is an oriented wire with numerical markers. Such a wire that is folded on itself locally defines a secondary structure. The main secondary structure elements of a protein are helices (e.g., the α-helix) and strands (β structures). The wire has only one dimension, but the secondary structure is projected on a plane so that the succession of the secondary structure elements of a protein can be viewed as a bidimensional formation. The three-dimensional (3D) structure of the protein is the third level of protein structure (tertiary structure). Finally, some proteins gain their biological activity when associated in oligomeric assemblies consisting of several subunits, each of these subunits corresponding to a single peptide chain, which defines the quaternary structure of the protein. This is the case for both circulating proteins such as hemoglobin and membrane receptors, including ion channel receptors for neurotransmitters. In most cases, the interaction between protein subunits involves the side chains of specific amino acid residues and is not covalent.
URL: https://www.sciencedirect.com/science/article/pii/B9780128001110000084
8.4.3 Peptides
A chain of amino acids connected using an amide bond is called a peptide bond. In some tumor cells, a number of peptide receptors are highly expressed. Some examples of peptide receptors include somatostatin peptide, gastrin related peptide, vasoactive intestinal peptide, etc. The drug–peptide conjugation effectively delivers therapeutic agents to the target site through interaction with peptide receptors. The prostate particular membrane antigen (PSMA) is widely present in most prostate cancer cells (Sewald and Jakubke, 2015).
Tian et al. developed a targeted anticancer formulation using peptide as a ligand. The developed peptide ligand modifies solid lipid nanoparticles loaded with atorvastatin calcium (ATC). The ATCCSK solid lipid nanoparticles (SLNs) were fabricated by coupling the peptide ligand CSKSSDYQC (CSK). It resulted that CSK-SLN exhibited a more efficient cellular uptake across the Caco-2/HT2a cocultured cell monolayer than compared with unmodified SLN and proved to be a potential carrier for transportation of the drug across the intestinal barrier. The CSK-SLNs showed a more effective cellular uptake across the Caco-2/HT29 cocultured cell monolayer as evidenced by confocal laser microscopy (Tian et al., 2016).
Following absorption, the mechanisms were studied using a modified in situ perfusion method in rats, which exhibited the segment-dependent absorption characteristics of ATC. The values of the ATC CSK-SLNs were found to be higher (2.99-fold) in comparison with the ATC solution. The outcome revealed that CSK-modified SLNs will be promising carriers for the transportation of drugs across intestinal barriers Fig. 8.10 (Tian et al., 2016).
Figure 8.10. Images of confocal microscopy.
Cellular uptake of solid lipid nanoparticles and CSK-solid lipid nanoparticles (200 mg/mL) by Caco-2/HT29 cocultured cells for dissimilar incubation times.
Source: Adapted with permission from Tian, Q., Ding, F., Guo, L., Wang, J., Wu, F., Yu, Y., 2016. Targeted solid lipid nanoparticles with peptide ligand for oral delivery of atorvastatin calcium. RSC Adv. 6 (42), 35901–35909.Alexander et al. developed a targeted anticancer formulation using peptide as a ligand. Cocomplexation of the EGFR-targeting peptide, GE11R9, with the endosome-disruptive 599 peptides facilitated the specific uptake of siRNAs into oral cancer cells. Therefore, when administered systemically to mice bearing xenograft oral tumors, it significantly enhanced the CIP2A silencing (Alexander-Bryant et al., 2017). The enhancement in the delivery of bioactive siRNAs to xenograft oral cancer tumors using dual peptide carrier is shown in Fig. 8.11.
Figure 8.11. The dual peptide carrier surges bioactive siRNAs delivery to xenograft oral cancer tumors following systemic administration.
(A) Representative in vivo images of siRNA biodistribution in mice and (B) quantitative analysis of tumor fluorescence 1–48 h posttreatment (C) Real-time PCR analysis of relative CIP2A mRNA levels in excised xenograft tumor tissues, 48 h posttreatment with dual peptide+Cy5.5-siCIP2A, 599+Cy5.5-siCIP2A.
Source: Adopted with permission from Alexander-Bryant, A.A., Zhang, H., Attaway, C.C., Pugh, W., Eggart, L., Sansevere, R.M., Andino, L.M., Dinh, L., Cantini, L.P., Jakymiw, A., 2017. Dual peptide-mediated targeted delivery of bioactive siRNAs to oral cancer cells in vivo. Oral Oncol. 72, 123–131.URL: https://www.sciencedirect.com/science/article/pii/B978012817909300008X
Biologically Important Peptides
Peptides have important functions, both in plants and animals. Generally, peptides are chains of amino acids linked by peptide bonds; however, some of them have peculiar characteristics, such as atypical peptide bonds, unusual amino acids or amino acid derivatives, formation of cyclic structures, etc.
The number and type of amino acids, their sequence, spatial arrangement, and their biological activity are important determinants of the functional role of peptides. Glutathione is a peptide widely distributed in nature, found in bacteria, plants, and animals. This tripeptide is composed by glutamic acid, cysteine, and glycine. Glutamic acid is bound to the amine group of cysteine by an atypical peptide bond, which involves the distal or γ carboxyl group of glutamic acid.
When oxidized, glutathione forms a disulfide bridge (SS) with another molecule of glutathione in a reaction that is reversible. Glutathione participates in enzymatic redox systems. It contributes to the prevention of oxidative damage in blood cells and tissues.
Many hormones are peptides. Table 3.1 presents a list of some of them. Another interesting group of peptides are the enkephalins, which are released by the central nervous system and produce analgesia by binding to specific brain receptors. Many antibiotics, substances synthesized by microorganisms that have toxic effects on other organisms, are peptides or contain a peptide as part of their molecule. Some of these antibiotics have a cyclic structure and often contain d-amino acids. Certain species of fungi produce peptides highly toxic to humans (α amanitin).
Table 3.1. Some Peptide Hormones
| Name | Number of amino acids | Function |
|---|---|---|
| Angiotensin II | 8 | Hypertensor |
| Vasopressin | 9 | Water balance |
| Oxytocin | 9 | Uterine contraction |
| Bradikinin | 9 | Hypotensor |
| Kalllidin | 10 | Hypotensor |
| Gastrin I | 17 | Gastric secretion of HCl |
| Melanocyte stimulant (β MSH) | 18 | Increases melanin |
| Secretin | 27 | Pancreatic juice secretion |
| Glucagon | 29 | Hyperglycemic |
| Calcitonin | 32 | Reduces Ca level in blood |
| Cholecystokinin–pancreoenzymin | 33 | Contraction of gall bladder; secretion of pancreatic enzymes |
| Adrenocorticotrophin | 39 | Stimulate adrenal cortex |
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2.3 THE BASIS OF PROTEIN STRUCTURE
2.3.1 Levels of protein structure
Four separate levels of protein structure can be determined: these are the primary, secondary, tertiary and quaternary structures.
The primary structure is the sequence of amino acids making up the protein: a peptide bond connects the α-carboxyl group of each amino acid to the α-amino group of the next in the chain
(2.1)
Since a molecule of water is lost when two free amino acid molecules undergo this condensation reaction, only their residues are linked. A molecule consisting of two amino acid residues joined by a peptide bond is called a dipeptide. Several residues linked in this way form an oligopeptide, while a chain of many amino acid residues linked together is termed a polypeptide. The covalent backbone of such a structure consists of α-carbon atoms linked by peptide bonds, the R groups sticking out from the chain. Each peptide chain has one free amino end (the N-terminus, which is regarded as belonging to the first amino acid in a peptide chain of any length) and one free carboxyl end (the C-terminus). All the other α-amino and α-carboxyl groups present are involved in peptide bonds. For example:
Proteins may contain one or more polypeptide chains, each one having a specific primary structure. Although a two-dimensional representation of a polypeptide chain can give the impression that the backbone is linear, it should be understood that this is not so. The even distribution in three-dimensional space of the single covalent bonds about the carbon and nitrogen atoms in the backbone means that no two bonds emerging from the same atom will be diametrically opposite each other (see section 2.2.2). Molecules may rotate freely about single covalent bonds, so an unlimited number of arrangements of a polypeptide chain in space are possible. However, some of these will be more stable than others, so are more likely to exist. Secondary structure refers to regular, repeating patterns formed by the backbone of at least part of a polypeptide chain and stabilized by hydrogen bonding.
Certain amino acids cannot be accommodated in these regular arrangements, so the secondary structure is disrupted wherever they occur. Again the possibility of free rotation about a bond at each point of disruption suggests that a great number of different structures could result, but in fact each polypeptide chain is found to have a single, characteristic, three-dimensional structure. This is termed the tertiary structure and, once formed, it may be stabilized by bonding between amino acids which find themselves in close proximity. It should be noted that amino acids which are widely separated in the primary structure may be close together in space, because of the twists of the polypeptide chain.
Several identical or non-identical polypeptide chains may then be linked together to form the actual protein. The complete three-dimensional structure, including the interactions between the component polypeptide chains, is termed the quaternary structure.
2.3.2 Bonds involved in the maintenance of protein structure
A single covalent bond is formed by the sharing of a pair of electrons between two atoms, each atom contributing one electron to the pair. By means of such a sharing arrangement, involving one or more covalent bonds, an atom can achieve an arrangement of electrons round its nucleus identical to that of an inert gas and thus become chemically stable. Two atoms of given identity, when linked by a single covalent bond, are located a characteristic distance apart, this distance being known as the bond length. If two atoms share two pairs of electrons between them, then a double covalent bond is formed. In this case the bond length is less than for the equivalent single bond. Molecules can rotate about single covalent bonds but not about double covalent bonds, which are more rigid.
The primary structure of a protein consists of amino acid residues linked by covalent peptide bonds. Covalent disulphide bridges (–S–S–), linking cysteine residues, are often involved in the maintenance of tertiary structure. In a very few instances, disulphide bridges may also link the separate polypeptide components of a protein (see sections 3.1.4 and 5.1.2).
An alternative way by which an atom might achieve stability by obtaining the same electron structure as an inert gas is for it to gain or lose a number of electrons, i.e. to form an ion. Ions which are formed by loss of electrons from an atom will have a net positive charge and are called cations while those formed by the addition of electrons will have a negative charge and are termed anions. The magnitude of the charge will depend on the number of electrons transferred.
An electrostatic interaction occurs between each pair of ions in the same medium. The force (F) between two ions A and B in dilute solution is given by Coulomb’s law:
(2.2)F=ZAZBe2/Dr2
where ZA is the number of unit charges carried by ion A, ZB the number carried by ion B, e is one unit of electronic charge, r is the distance between the two ions and D is the dielectric constant of the medium. Ions with like charge repel each other while those of opposite charge attract.
Thus the tertiary and quaternary structures of proteins could involve electrostatic linkages between amino acids with side chains of opposite charge (e.g. between lysine and glutamic acid). In fact, in an aqueous environment it is energetically more favourable for a charged group to form linkages with surrounding water molecules rather than with another charged group in the protein. However such linkages do occur in hydrophobic regions of proteins (see below) and so could play an important role in the stabilization of the three-dimensional structure.
It often happens that covalent bond formation does not lead to an equal sharing of a pair of electrons between two atoms. The electrons may be associated with one of the components more than the other, producing a slight separation of charge between the atoms, called a dipole effect. The atom having the greater association with the shared pair of electrons will have a partial negative charge and can thus form weak electrostatic linkages, as can the other atom, which will have a partial positive charge.
The most important example of this phenomenon is the hydrogen bond. The oxygen atoms of –OH or –C=O groups have a slight negative charge, while the hydrogen atoms of >NH or –OH groups have a slight positive charge. Hence a weak electrostatic linkage can be formed between the oxygen atom in one group and the hydrogen atom in another, e.g. –C=O⋯·H–O–. The bond energy involved is small, but sufficient to add stability to a structure.
All the water molecules present in an aqueous medium link by means of hydrogen bonding to produce a huge three-dimensional network. Hydrogen bonds can be formed between groups in polypeptides and the surrounding water molecules, as well as between different components within polypeptide chains. Such bonds can help to stabilize the secondary, tertiary and quaternary structures of proteins.
Although the arrangement of electrons about an atom may, on average, be symmetrical, the constant fluctuations in electron distribution mean that the arrangement is likely to be asymmetrical at any given instant. Hence a dipole exists, however momentarily, and this induces a corresponding effect in all neighbouring atoms, causing them to attract each other. This is true of all atoms, even those of inert gases.
However, when two atoms come into very close proximity, the repulsion between their respective clouds of surrounding electrons is greater than the induced attraction. There is an optimal distance between two non-bonding atoms, known as the van der Waals contact distance, when the forces of attraction and repulsion are equal. These forces are known as London dispersion forces and the weak linkages resulting from dipole effects are sometimes termed van der Waals bonds. These play an important part in governing which three-dimensional structure is taken up by a protein.
Non-polar, or hydrophobic bonds also have a considerable influence on protein structure. These bonds are not formed as a result of any direct interaction between atoms and may be best considered from the point of view of the complete protein/solvent mixture. The network of hydrogen bonds linking water molecules to each other confers great stability, so the most stable structure for a protein in aqueous solution will be that which gives the greatest possibility of hydrogen bonding between the protein molecule and the surrounding water molecules. Non-polar side chains of amino acids cannot form hydrogen bonds, so the contact between these and the water molecules must be minimized. Two such side chains in close proximity will tend to come even closer, forcing out all water molecules from between them, so that a single non-polar region is formed from the two originally present. Many non-polar side chains may be incorporated into a single non-polar zone, creating a hydrophobic micro-environment that is quite different from the micro-environments in other parts of the protein molecule.
In the case of metalloenzymes a further type of bond, the co-ordinate bond, needs to be mentioned. Like the covalent bond, this involves the sharing of a pair of electrons between two atoms, but in this case both electrons come originally from the same atom. A metal atom can accept pairs of electrons in this way from donor groups, or ligands, until it has the required number of electrons at a particular level. (A ligand is simply something which binds, the word having the same Latin root as the name of the group of enzymes called ligases.) The electrons which may be lost by a metal atom to form an ion are at a different level from those involved in coordinate bond formation, so the two processes are quite distinct.
The bonds involved in the maintenance of protein structure will be discussed further, in the light of experimental evidence, in section 2.5.2. In general, the three-dimensional structure taken up by a protein will be that which is energetically most favourable, taking into account all possible interactions involving the types of bond discussed in the present section.
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