Nonpolar side chains

Ammo acids with nonpolar side chains... 

Nonpolar side chains Glycine is the smallest anino acid because it has no side chain. The main service it offers is to the polypeptide chain itself. It can add length and flexibility to a polypeptide without sacrificing strength or making spatial demands of its own. 

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. 

What about tertiary structure Why does any protein adopt the shape it does The forces that determine the tertiary structure of a protein are the same forces that act on ail molecules, regardless of size, to provide maximum stability. Particularly important are the hydrophilic (water-loving Section 2.13) interactions of the polar side chains on acidic or basic amino acids. Those acidic or basic amino acids with charged side chains tend to congregate on the exterior of the protein, where they can be solvated by water. Those amino acids with neutral, nonpolar side chains tend to congregate on the hydrocarbon-like interior of a protein molecule, away from the aqueous medium. 

Of the 20 amino acids, 11 have polar side chains (color screened), and 9 have nonpolar side chains. One, proline, has a unique ring structure. Under the name of each amino acid is its three-letter abbreviation. 

Hydrophobic interactions, on the other hand, are strong, indifferent to local details, and are relatively long range. If transient direct or water-separated contacts occur between nonpolar side chains, the net effect could be local organization and an overall compaction of the polypeptide chain. Whereas the strengths of hydrophobic interactions must be considerably reduced in 8 M urea, they clearly are not eliminated, as evidenced by the persistence of lipid bicelles. Thus hydrophobic interactions probably play some role in persistent global structure, the importance of which can be tested by replacing multiple hydrophobic side chains with similarly shaped polar ones. 

Among these drugs, the dihydrofolate reductase (DHFR) inhibitors are used clinically with a certain amount of success. They belong to two major classes the classical antifolates which feature a polar amino-acid side chain terminus and those containing nonpolar side chains, called lipophilic or nonclassical anti-folates. 

Values of /c2, the maximal rate constant for disappearance of penicillin at pH 10.24 and 31.5°, and Ka, the cycloheptaamylose-penicillin dissociation constant are presented in Table VII. Two features of these data are noteworthy. In the first place, there is no correlation between the magnitude of the cycloheptaamylose induced rate accelerations and the strength of binding specificity is again manifested in a rate process rather than in the stability of the inclusion complex. Second, the selectivity of cycloheptaamylose toward the various penicillins is somewhat less than the selectivity of the cycloamyloses toward phenyl esters—rate accelerations differ by no more than fivefold throughout the series. As noted by Tutt and Schwartz (1971), selectivity can be correlated with the distance of the reactive center from the nonpolar side chain. Whereas the carbonyl carbon of phenyl acetates is only two atoms removed from the phenyl ring, the reactive center... 

The first category is composed of the nine amino acids having nonpolar side chains, identified as those with side chains that are largely hydrocarbon in nature. The single exception is methionine, which contains a sulfur atom in its side chain. This is not a problem, since sulfur atoms are quite hydrophobic. Basically, hydrocarbons do not like water hydrophobic means water-hating. Think about fats, oils, waxes. 

HYDROPHOBIC INTERACTIONS. These bonding interactions arise from the tendency of nonpolar 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 tightly bound water molecules from these apolar side-chain moieties. The hydrophobic effect is thermodynamically driven by the increased disorder i.e., A5 > 0) of the system, thereby overcoming the unfavorable enthalpy change i.e., AH < 0) for water release from the apolar groups. 

The folding of proteins into their characteristic three-dimensional shape is governed primarily by noncovalent interactions. Hydrogen bonding governs the formation of a helices and [) sheets and bends, while hydrophobic effects tend to drive the association of nonpolar side chains. Hydrophobicity also helps to stabilize the overall compact native structure of a protein over its extended conformation in the denatured state, because of the release of water from the chain s hydration sheath as the protein... 

Each of these amino acids has a nonpolar side chain that does not bind or give off protons or participate in hydrogen or ionic bonds (see Figure 1.2). The side chains of these amino acids can be thought of as "oily" or lipid-like, a property that promotes hydrophobic interactions (see Figure 2.9, p. 18). 

In both carboxypeptidase A and thermolysin the active site Zn2+ is chelated by two imidazole groups and a glutamate side chain (Fig. 12-16). In carboxypeptidase A, Arg 145, Tyr 248, and perhaps Arg 127 form hydrogen bonds to the substrate. A water molecule is also bound to the Zn2+ ion. The presence of the positively charged side chain of Arg 145 and of a hydro-phobic pocket accounts for the preference of the enzyme for C-terminal amino acids with bulky, nonpolar side chains. The Zn2+ in thermolysin is also bound to two imidazole groups and that in D-alanyl-D-alanyl carboxypeptidase to three. 

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. 

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