Side chains of amino acids

Hydrophobic bonds, or, more accurately, interactions, form because nonpolar side chains of amino acids and other nonpolar solutes prefer to cluster in a nonpolar environment rather than to intercalate in a polar solvent such as water. The forming of hydrophobic bonds minimizes the interaction of nonpolar residues with water and is therefore highly favorable. Such clustering is entropically driven. The side chains of the amino acids in the interior or core of the protein structure are almost exclusively hydrophobic. Polar amino acids are almost never found in the interior of a protein, but the protein surface may consist of both polar and nonpolar residues. 

Fig. 4.9 A synthesis resulting in polypeptides (or compounds similar to polypeptides using amino-malonitrile and further adding hydrogen cyanide. In this process, R 15 may represent different side chains of amino acids...

Aromatic side chains of amino acids such as phenylalanine, tryptophan, and tyrosine are found in general in the interior of proteins, in hydrophobic regions. In some proteins they mediate helix-helix contacts. It is to be expected that agents containing aromatic groups could interact with proteins via aromatic-aromatic interactions, as for instance, proven by X-ray studies of biphenyl compounds which inhibit sickle-cell hemoglobin gelation. 

Global Softness and Local Softness (Side Chains) of Amino Acids Computed at MP2/6-311G(d,p) in Ref. [18]... 

Preliminary information useful in prodrug design has been obtained with amino acids attached to model aromatic amines. Thus, N-(naphthalen-2-yl) amides of amino acids (6.1, R=side chain of amino acid, R =H) proved to be of interest as test compounds to monitor peptidase activity such as ami-nopeptidase M (membrane alanyl aminopeptidase, microsomal aminopepti-dase, EC 3.4.11.2) [16][17], In the presence of purified rabbit kidney aminopeptidase M or human cerebrospinal fluid (CSF) aminopeptidase activity, the rate of hydrolysis decreased in the order Ala-> Leu->Arg->Glu-2-naphthyl-amide. Ala-2-naphthylamide, in particular, proved to be a good test compound, as its rate of hydrolysis was influenced by experimental conditions (preparation, inhibitors, etc.), as was the hydrolysis of a number of low-molecular-weight opioid peptides and circulating vasoactive peptides. 

Similarly, the 4-methoxy-2-naphthylamides of Leu, Ala, Arg, and Glu (6.1, R=side chain of amino acid, R =MeO) were used to assess the type and activity of aminopeptidase in homogenates of conjunctival, nasal, buccal, duodenal, ileal, rectal, and vaginal tissues from rabbits. This systematic comparison afforded a better understanding of the role of the aminopeptidase barrier in peptide absorption from oral vs. non-oral routes [18]. In a comparable manner, the y-glutamyltranspeptidase and dipeptidase activities were investigated in mammary tissue with the 4-nitroanilides of Leu, Met, Lys, Glu, and Asp (6.2, R=side chain of amino acid) [19]. 

The tendency of apolar side chains of amino acids (or lipids) to reside in the interior nonaqueous environment of a protein (or membrane/micelle/vesicle). This process is accompanied by the release of water molecules from these apolar side-chain moieties. The effect is thermodynamically driven by the increased disorder (ie., AS > 0) of the system, thereby overcoming the unfavorable enthalpy change (ie., AH < 0) for water release from the apolar groups. 

Interactions of side chains of amino acids through hydrogen bonds and ionic bonds. 

E. The a-helix is stabilized primarily by ionic interac tions between the side chains of amino acids. 

The binding pocket in chymotrypsin may be described as a hydrophobic pocket, since it is lined with the nonpolar side chains of amino acids. It provides a suitable environment for the binding of the nonpolar or hydrophobic side chains of the substrates. The physical causes of hydrophobic bonding and its strength are discussed in Chapter 11. 

To summarize, the binding sites of lysozyme and the serine proteases are approximately complementary in structure to the structures of the substrates the nonpolar parts of the substrate match up with nonpolar side chains of the amino acids the hydrogen-bonding sites on the substrate bind to the backbone NH and CO groups of the protein and, for lysozyme, to the polar side chains of amino acids. The reactive part of the substrate is firmly held by this binding next to acidic, basic, or nucleophilic groups on the enzyme. 

The side chains of amino acid residues in a protein may be changed at will by protein engineering (Chapter 14) and the consequent effects on binding and catalysis studied directly. This is the subject of Chapter 15, where it will be seen how the equations derived so far actually hold in practice and are used to analyze the data. There is direct evidence for enzyme-transition state complementarity. 

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