Principles of Protein Structural Organization - G. Schultz 1982

Amino Acids
Properties of Side Chains

The canonical Amino Acids differ only in their side chains. Each side chain is so specific that it cannot easily be replaced by any other. The properties of all standard side chains will be discussed below.

Gly increases The flexibility of the main chain. It is a unique amino acid that lacks a side chain and therefore does not exhibit Asymmetry at the C_а atom. The absence of a side chain allows Gly residues to adopt unusual dihedral angles (Fig. 2.3, a), leading to bends in the main chain. In addition, Gly residues can promote The formation of a tightly packed protein molecule chain. Probably for these reasons, the Gly residue has remained virtually unchanged during evolution.

The Alanine side chain contains a single methyl group. This is a small, nonpolar residue with no particular preference for being located in the interior or On the surface of a protein. Ala is the most abundant amino acid, apparently due to its simplicity and availability. Only Gly is simpler to obtain. However, the content of Gly in the chain is limited: an excess of it would lead to excessive lability of the main chain.

Rigidity of branched side chains. The nonpolar side chains of valine, isoleucine, and leucine are branched. The branching of large side chains determines their limited internal mobility. The Val residue contains branching at the C_β atom; its C_y methyl groups sterically interact with the main chain, reducing its mobility. The Ile residue is also branched at the C_β atom, with the branches differing from each other. Therefore, C_β in Ile serves as an additional asymmetric center. Since all biological reactions are stereospecific, only one stereoisomer is used (Fig. 1.2,6). The presence of Ile makes the main chain more rigid, much like the presence of Val. In the case of Leu, no significant steric interactions with the main chain occur because the side chain branching in this amino acid is located at the C_y atom. Rigid side chains are more easily fixed in a specific position; the decrease in Entropy ∆S_chain in this case is not as large (Sec. 3.5), which facilitates chain folding.

All aromatic residues contain a single intervening methylene unit. Phenylalanine carries the largest, fully nonpolar side chain. As with the other three aromatic side chains, There is a C_β-methylene group between C_а and the aromatic ring. Even with the methylene group present, the mobility of the side chain is noticeably restricted; without the intervening methylene group, the aromatic ring would create severe steric hindrance at the C_а atom, making the main chain overly rigid. Completely nonpolar Proline is a very specific residue because its side chain is covalently linked to the main chain. This results in an almost rigid Structure in which only minor ring distortions are possible. In addition, proline fixes the dihedral angle of rotation around the bond between C_а and the peptide nitrogen within a narrow range of ± 20°.

Tryptophan has the bulkiest side chain. Its slight polarity is due to the presence of a heterocyclic indole ring. The fairly flexible side chain of Methionine contains a single sulfur atom in a thioether group, which gives rise to a dipole moment. All of the largest nonpolar residues—Val, Ile, Leu, Phe, Pro, Trp, and to a lesser extent Met—are located predominantly in the interior of protein molecules.

Polar side chains form Hydrogen Bonds. Typical polar and neutral side chains are possessed by Cysteine, Serine, Threonine, asparagine, glutamine, and Tyrosine. Among them, Cys plays a special role because it is capable of forming cross-links (cystines) between different PARTS OF THE main chain by attaching to another Cys residue (Sec. 4.2). Ser and Thr residues carry hydroxyl groups that can form hydrogen bonds. In Thr, which possesses an asymmetric C_β atom, only one stereoisomer is active (Fig. 1.2,6). Asparagine and glutamine, bearing amide groups, are also capable of forming hydrogen bonds, with the amide groups functioning as hydrogen Donors and the carbonyl groups as acceptors. Compared to asparagine, glutamine has an extra methylene unit, which imparts greater mobility to the polar group and weakens its interaction with the main chain. The polar hydroxyl group of Tyr, which has a pK of 10.1, can dissociate at high pH values. Therefore, Tyr is somewhat analogous to a charged group: the hydrogen bonds it forms are quite strong. Neutral polar residues can be located both on the surface and in the interior of protein molecules. When located in the interior, they typically form hydrogen bonds with each other or with the polypeptide backbone (Sec. 3.6).

His is well-suited for catalytic purposes. Histidine contains a heterocyclic aromatic side chain with a pK of 6.0 (Table 1.1). In the physiological pH range, its imidazole ring can either remain uncharged or take up an H⁺ ion from solution. Since this addition occurs quite readily, histidine can act as a catalyst for Chemical Reactions. It has been established that it is present in most enzyme active sites.

Charged side chains are usually found on The surface of molecules. Aspartic and glutamic acid residues are negatively charged at physiological pH values. Due to its short side chain, the carboxyl group of Asp is quite rigidly fixed relative to the main chain. This may be the reason why the carboxyl groups of active sites belong primarily to Asp residues rather than Glu. As a rule, both residues are located on the surface of Proteins.

Most of the positively charged Lysine and Arginine residues are also located on the surface of protein molecules. These long and flexible residues usually lack a strictly fixed conformation. Highly mobile in the surrounding environment, they increase the solubility of protein globules. However, in some cases, the side chains of Lys and Arg participate in the formation of internal salt bridges and also contribute to catalysis. Due to their surface Location, Lys and Arg residues are more susceptible than others to attack by Enzymes that either modify their side chains or cleave the polypeptide chain on the carbonyl carbon side (Sec. 4.3).

Hydrophobicity depends on contact surface area and the number of dipoles. As indicated in Chapters 3 and 8, the folding process of a polypeptide chain depends on the hydrophobicity (nonpolarity) of the side chains, since the Formation of the Hydrophobic core of the globule appears to be one of the main driving forces of folding. Kozman [15] and later Nozaki and Tanford [16] determined this hydrophobicity by measuring The change in Free energy upon The transfer of amino acids from Water to organic Solvents. To obtain the free energy difference ∆G_transfer for a side chain, THE CONTRIBUTION OF the main chain must be subtracted. This can be done by subtracting the value for Gly. The results are presented in Table 1.1.

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Fig. 1.8. Water-accessible surface [17] of an amino acid side chain as a function of its hydrophobicity [16], i.e., as a function of the Free energy of transfer from water to ethanol or dioxane, which are assumed to mimic conditions in the interior of a protein. The water-accessible surface is defined in Fig. 1.9.

Fig. 1.9. Water-accessible surface of a protein (or side chain).

The protein surface is described by the envelope of the Van der Waals radii of the atoms located on the surface (indicated by dots). The interior of the protein is hatched. Water molecules are represented as spheres with a radius of 1.4 Å. The "water-accessible surface" is defined as the area swept out by the center of a water molecule as it rolls over the van der Waals surface of the protein (or side chain). Note that in crevices, there are Regions of the protein (or side chain) that are inaccessible to water molecules.

As Chothia [17] showed (Fig. 1.8), for fully nonpolar side chains, there is a linear relationship between ∆G_transfer and the water-accessible surface area. The water-accessible surface area is defined in Fig. 1.9. A similar relationship, but with a decrease in ∆G_transfer of approximately 1.5 kcal/mol, is found for residues containing a single dipole, such as Ser, Thr, Met, Tyr, and Trp (Sec. 3.5). THE POSITION OF Trp in Fig. 1.8 shows that the indole ring represents a weak dipole. The dipole of Met appears to be stronger. This is confirmed by the detection of two hydrogen bonds with Met-180 in Chymotrypsin [18].