Fundamentals of Molecular Biology. Part 1: Cell Molecular Biology - A. N. Oagurtsov 2011

Nucleic Acids and Proteins
Proteins. Classification of Amino Acids

Proteins are irregular polymers whose monomers are $a-L-Amino\; Acids$.

5.4.1. Structure of Amino Acids. Each amino acid contains an amino group attached to a carbon atom, to which a carboxyl group, a hydrogen atom, and an amino acid side chain are also bonded. This configuration is common to all amino acids. The amino group may be attached to the carbon atom immediately adjacent to the carboxyl group (alpha-carbon), or to the second carbon atom, and so on (Figure 69).

The carbon atoms are numbered using Greek letters; depending on which position the amino group is attached to, the molecule is referred to as an alpha-amino acid, a beta-amino acid, and so on. Proteins are exclusively composed of alpha-amino acids.

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Figure 69 - Amino acid structure: a - $a-amino\; acid$, b - $y-amino\; acid$

The carboxyl group exhibits acidic properties; in aqueous solution, it dissociates to release a proton and form a negatively charged $COO-$ group. Conversely, the amino group ($NH$₂) is basic and can accept a proton to become positively charged. Within an amino acid molecule, a proton can transfer from the carboxyl group to the amino group, forming what is known as a zwitterion (a dipolar ion). In aqueous solutions, amino acids predominantly exist as zwitterions (Figure 70).

Importantly, amino acid molecules can differ in their spatial configuration, a phenomenon known as stereoisomerism. These molecules are designated as D-isomers and L-isomers (dextrorotatory and levorotatory, respectively) (Figure 71).

Figure 70 - Diagram of an amino acid zwitterion

D- and L-isomers are mirror images of each other and cannot be superimposed in three-dimensional space without being rotated through a fourth dimension. In schematic diagrams (such as Figure 70), bonds pointing toward the viewer in front of the page are conventionally represented by a wedge, while bonds pointing away behind the plane of the page are shown with dashed lines.

Figure 71 - Amino acid isomers: a - L-isomer, b - D-isomer

In living organisms, all Amino acids are L-isomers—specifically, 19 chiral asymmetric L-amino acids, whereas the twentieth amino acid, Glycine, is achiral. D-isomers are relatively rare and serve specialized Functions, such as components of certain Antibiotics.

Altogether, living Cells utilize 20 standard amino acids (or more precisely, 19 Amino Acids and one imino acid, Proline).

The Abbreviations for Proteinogenic Amino Acids are listed in Table 5, and their side-chain structures are illustrated in Figure 72.

Table 5 - Names and Abbreviations of Amino Acids

Amino acids consist of a central alpha-carbon atom ($Ca$ or $C$_a) and three functional groups: an amino group, a carboxylic acid group, and an amino acid side chain. Within the protein backbone, the amino group of each amino acid is joined via a peptide bond to the carboxyl group of the next amino acid in the sequence.

Figure 72 - Side chains of standard amino acid residues

The twenty standard amino acids involved in METABOLISM/35.html">Protein Biosynthesis—hence called proteinogenic amino acids—vary in both chemical and structural properties. By combining these amino acids, cells can achieve the desired protein globule conformation while ensuring structural stability.

Furthermore, side chains required to carry out specific biochemical reactions can be precisely positioned at specific locations along the protein chain.

Amino acids are typically classified into the following groups:

✵ nonpolar (glycine, proline, alanine, valine, leucine, isoleucine),

✵ aromatic (phenylalanine, tyrosine, tryptophan),

✵ polar uncharged (serine, threonine, cysteine, methionine, asparagine, glutamine),

✵ charged (negatively charged: aspartic acid and glutamic acid; positively charged: lysine and arginine).

✵ histidine, due to its Specificity, can be classified as either a polar uncharged or a positively charged amino acid.

5.4.2. Special amino acids. Four amino acids—glycine, proline, cysteine, and methionine—are often referred to as special amino acids because their presence in a protein chain is associated with specific functions.

The amino acids glycine (Gly, Figure 73) and proline (Pro, Figure 74) perform specific structural functions in "building" the protein globule.

Figure 73 - STRUCTURE OF THE amino acid glycine (Gly)

Glycine is the smallest amino acid, lacking a side chain. As a result, the polypeptide chain is more labile (flexible) at the site where glycine is located.

Figure 74 - Structure of The amino acid proline (Pro)

Glycine is utilized in Regions of the protein chain that require maximum bending to achieve the tightest conformation, and where Other Amino Acids simply would not fit due to the dense packing of surrounding atoms, as is the case, for example, in the tightly coiled triple-helical cable of Collagen shown in Figure 75.

Figure 75 - Structural Features of glycine and proline

Proline is the unique cyclic amino acid (more precisely, proline is an imino acid) whose side chain is attached to the polypeptide chain by two covalent bonds (CH₂-^aC and CH_2-N). Proline forms a rigid bend (kink) in the protein chain. In collagen, such kinks facilitate The formation of a tight triple protein helix.

The amino acids cysteine and methionine contain sulfur atoms (Figures 76, 77, 79).

Cysteine (Cys) is the most reactive amino acid, containing a thiol (SH) group.

Figure 76 - Structure of the amino acid cysteine (Cys)

Two cysteine residues from different regions of a protein chain can form a covalently linked disulfide bridge.

Figure 77 - Structure of the amino acid methionine (Met)

Cysteine is also involved (along with serine) in the formation of catalytic active sites in Enzymes. Cysteine effectively interacts with Metal Ions and is utilized in forming metal-binding sites.

Methionine (Met) contains a hydrophobic sulfur atom. The synthesis of any protein chain invariably begins with methionine (specifically, formylmethionine, as shown in Figure 78(a)).

Figure 78 - Structural formulas: a - formylmethionine, b - guanidine, c - imidazole

Figure 79 - Structural features of cysteine and methionine

Methionine is often used similarly to hydrophobic aliphatic amino acids to facilitate protein folding. The sulfur atom is nucleophilic and can interact with certain types of metal ions.

These properties of cysteine and methionine are utilized in the small electron-carrying protein ferredoxin (Figure 79). The disulfide bond is shown in the upper right corner of the ferredoxin molecule, while four cysteines anchor a cluster consisting of one iron atom and four sulfur atoms (shown in dark gray in the center of ferredoxin). Two methionine residues flank the cluster, stabilizing it within the Cell/13.html">Protein Structure.

5.4.3. Nonpolar and aromatic amino acids. The amino acids alanine (Ala), valine (Val), leucine (Leu), and isoleucine (Ile) (Figures 80 - 83) are nonpolar aliphatic amino acids whose side chains are saturated with hydrocarbon groups and differ in shape and size.

Figure 80 - Diagram of the amino acid alanine (Ala)

The amino acids alanine, valine, leucine, and isoleucine impart relative rigidity and inflexibility to the polypeptide chain and are strongly hydrophobic.

Often, it is precisely the presence of these hydrophobic amino acids that drives the folding of the protein chain.

Figure 84 illustrates THE POSITION OF these amino acids within the Insulin globule, where they form a tightly packed cluster inside the protein.

Figure 81 - Diagram of the amino acid valine (Val)

Figure 82 - Diagram of the amino acid isoleucine (Ile)

Figure 83 - Diagram of the amino acid leucine (Leu)

Although one can envision A large number of other similar amino acid residues differing in the number and arrangement of hydrocarbon groups, only these four amino acids are genetically encoded in natural biosystems.

Figure 84 - Structural features of isoleucine, leucine, alanine, and valine

Phenylalanine, tyrosine, and tryptophan. The amino acid residues of phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp) contain aromatic groups (Figures 85 - 87).

Much like aliphatic amino acids, these amino acids are hydrophobic and also contribute to the folding of protein chains.

The aromatic rings of these amino acids are frequently stacked on top of one another or over DNA bases (which also possess a cyclic structure) and serve to ensure the specificity of binding sites for interactions between the given protein and other protein molecules or Nucleic Acids.

Figure 85 - Diagram of the amino acid phenylalanine (Phe)

Figure 86 - Structure of the amino acid tyrosine (Tyr)

Figure 87 - Structure of the amino acid tryptophan (Trp)

In addition to its aromatic ring, tyrosine contains a hydroxyl group. This imparts unique properties that facilitate interactions with small organic molecules. Active sites containing tyrosine are capable of simultaneously binding to the hydrophobic regions of ligands and forming Hydrogen Bonds with them.

Figure 88 shows a diagram of a bacterial porin molecule embedded in a lipid membrane, which is schematically represented as a gray rectangle.

Figure 88 - Structural features of phenylalanine, tyrosine, and tryptophan

Aromatic amino acids are distributed along the perimeter of the porin, forming distinct zones on the protein surface that interact with the Hydrophobic core of the biomembrane.

5.4.4. Polar uncharged amino acids. Polar uncharged amino acids include serine (Ser), threonine (Thr), asparagine (Asn), glutamine (Gln), and histidine (His) (Figures 89 – 93).

Figure 89 - Structure of the amino acid serine (Ser)

Figure 90 - Structure of the amino acid threonine (Thr)

Figure 91 - Structure of the amino acid asparagine (Asn)

Figure 92 - Structure of the amino acid glutamine (Gln)

Figure 93 - Structure of the amino acid histidine (His)

The amino acid residues of serine, threonine, histidine, asparagine, and glutamine participate in hydrogen bonding. As a rule, these amino acids are located On the surface of the protein globule, where they interact with surrounding Water molecules (Figure 94).

Polar uncharged amino acids are frequently employed to link protein structures together and to establish specific interactions with other molecules.

Histidine performs specialized functions. It contains an imidazole group (Figure 78(b)) that can exist in either a charged or neutral state under slightly varying conditions. In its neutral form, histidine combines an electrophilic protonated secondary nitrogen—capable of acting as a Hydrogen bond donor—with a strongly nucleophilic tertiary nitrogen that can serve as a hydrogen bond acceptor. Because the tertiary nitrogen is frequently protonated in the Cytosol, histidine is sometimes classified among positively charged amino acids.

Figure 94 - Structural features of histidine, serine, asparagine, threonine, and glutamine

Histidine occurs relatively infrequently in proteins. It is primarily involved in the formation of specialized catalytic active sites in enzymes.

For example, Figure 94 shows how histidine is used in the proteolytic enzyme Trypsin to activate the amino acid serine. Normally, the hydroxyl group of serine is inactive, but in its activated form, serine participates in catalytic reactions that involve either adding or abstracting a hydrogen atom.

Histidine also interacts effectively with metal ions and is used to form specific metal-binding sites.

5.4.5. Charged amino acids. Charged amino acids include aspartic acid (Asp) and glutamic acid (Glu) as negatively charged amino acids, and lysine (Lys) and arginine (Arg) as positively charged amino acids.

Aspartic and glutamic acids contain carboxylic acid groups (Figures 95–97).

Figure 95 - Cytology/cytology/92.html">SCHEMATIC STRUCTURE OF aspartic acid (Asp)

Figure 96 - Schematic structure of glutamic acid (Glu)

Under normal physiological conditions at neutral pH, these amino acid residues are ionized and negatively charged. They are typically found on The surface of proteins (Figure 97) and are frequently involved in biochemical catalysis and the tight binding of metal cations.

Figure 97 - Structural features of aspartic and glutamic acids

Lysine and arginine. The positively charged amino acids lysine and arginine bear basic groups at the end of a long hydrocarbon chain (Figures 98–100).

Figure 98 - Schematic structure of the amino acid lysine (Lys)

Figure 99 - Schematic structure of the amino acid arginine (Arg)

The amino group at the terminus of lysine and the guanidino group (Figure 78(6)) at the terminus of arginine are ionized under physiological conditions at normal pH, carrying a positive charge. Lysine and arginine are located on the surface of protein globules and are used to recognize negatively charged molecules.

Figure 100 - Structural features of lysine and arginine (the DNA molecule is shown in dark gray)

In particular, arginine is used for binding proteins to nucleic acids—Figure 100 illustrates a repressor protein bound to a double-stranded DNA helix.

The long, flexible hydrocarbon chain of arginine also participates in hydrophobic interactions with other hydrophobic molecules.