Hydrophobic nonpolar amino acid

Leucine (Leu or L) ((A)-2-amino-4-methyl-pentanoic acid) is a neutral, aliphatic amino acid with the formula HOOCCH(NH2)CH2CH(CH3)2 and with a hydrocarbon side chain. Leu is classified as a hydrophobic (nonpolar) amino acid. ... 

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. 

The characteristic coiled-coil motifs found in proteins share an (abcdefg) heptad repeat of polar and nonpolar amino acid residues (Fig. 1). In this motif, positions a, d, e, and g are responsible for directing the dimer interface, whereas positions b, c, and f are exposed on the surfaces of coiled-coil assemblies. Positions a and d are usually occupied by hydrophobic residues responsible for interhelical hydrophobic interactions. Tailoring positions a, d, e, and g facilitates responsiveness to environmental conditions. Two or more a-helix peptides can self-assemble with one another and exclude hydrophobic regions from the aqueous environment [74]. Seven-helix coiled-coil geometries have also been demonstrated [75]. 

Valine (possibly other nonpolar amino acids) Surface tension increase To hydrophobic regions Weak stabilization... 

Now we can ask what is likely to happen to the three-dimensional structure of a protein if we make a conservative replacement of one amino acid for another in the primary structnre. A conservative replacement involves, for example, substitution of one nonpolar amino acid for another, or replacement of one charged amino acid for another. Intnitively, one would expect that conservative replacements would have rather little effect on three-dimensional protein structure. If an isoleucine is replaced by a valine or leucine, the structnral modification is modest. The side chains of all of these amino acids are hydrophobic and will be content to sit in the molecnlar interior. This expectation is borne out in practice. We have noted earlier that there are many different molecnles of cytochrome c in nature, all of which serve the same basic function and all of which have similar three-dimensional structnres. We have also noted the species specificity of insulins among mammalian species. Here too we find a number of conservative changes in the primary structure of the hormone. Although there are exceptions, as a general rule conservative changes in the primary structnre of proteins are consistent with maintenance of the three-dimensional structures of proteins and the associated biological functions. 

FIGURE 11-3 Fluid mosaic model for membrane structure. The fatty acyl chains in the interior of the membrane form a fluid, hydrophobic region. Integral proteins float in this sea of lipid, held by hydrophobic interactions with their nonpolar amino acid side chains. Both proteins and lipids are free to move laterally in the plane of the... 

Peripheral proteins are loosely associated with the membrane through electrostatic interactions and hydrogen bonds or by covalently attached lipid anchors. Integral proteins associate firmly with membranes by hydrophobic interactions between the lipid bilayer and their nonpolar amino acid side chains, which are oriented toward the outside of the protein molecule. 

Location of nonpolar amino acids in proteins In proteins found in aqueous solutions, the side chains of the nonpolar amino acids tend to cluster together in the interior of the protein (Figure 1.4). This phenomenon is the result of the hydrophobicity of the nonpolar... 

Location of polar and nonpolar amino acid residues The interior of the myoglobin molecule is composed almost entirely of nonpolar amino acids. They are packed closely together, forming a structure stabilized by hydrophobic interactions between these clustered residues (see p. 19). In contrast, charged amino acids are located almost exclusively on the surface of the molecule, where they can form hydrogen bonds, with each other and with water. 

The most hydrophobic integral membrane proteins can be extracted into organic solvents such as mixtures of chloroform and methanol. One such proteolipid protein, the 23.5-kDa lipophilin, accounts for over half the protein of myelin.57 182 The purified protein from rat brain contains 66% of nonpolar amino acids and six molecules of covalently bound palmitic acid and other fatty acids per peptide chain in thioester linkage to cysteine side chains. This protein evidently has four transmembrane helical segments with the six fatty acid chains incorporated into the membrane bilayer. It also has cytoplasmic and extracellular loops, one of which binds inositol hexakisphosphate (Ins P-6). (Fig. 11-9).183 The myelin proteolipid is an essential component of the myelin sheath and defects in this protein are associated with some demyelinating diseases57 which are discussed in Chapter 30. 

In Mb, heme is located in the heme pocket via multiple noncovalent interactions such as Fe-His coordination, hydrophobic contacts with several nonpolar amino acid residues, and hydrogen bonding between heme propionates and polar amino acids (69). Therefore, the hemin can be easily removed from the heme pocket under acidic conditions to give apomyoglobin (apoMb) (70, 71). Over the past three decades, a variety of artificial iron porphyrins and porphyrinoids have been incorporated into the apoprotein to reconstitute the... 

These results on amino acid solubilisation in reversed micelle solutions have indicated clearly that such systems could be useful for the recovery, separation and concentration of small, charged biological molecules from aqueous media. Furthermore, they have shed some light on the role that hydrophobic interactions will play in the solubilisation of more complex molecules such as proteins, which have a distribution of polar and nonpolar amino acid residues over their surfaces. 

Fig. 2.11. Correlation between accessible surface area and hydrophobicity expressed as free energy of transfer between organic solvent and water for various hydrocarbons (iunlabeled dots), and for amino acids. The accessible surface area is obtained by rolling a water molecule (sphere 1.4 A) around the solute molecule and calculating the contact surface. The slopes of the lines are 25 cal A-2 for hydrocarbons and polar amino acids and 22 cal A-2 for nonpolar amino acids [137]...

Oligomers of glycine show little appreciable retention on octyl silica with 20 mM phosphate buffers over the pH range 2.10-7.83 (46), or on octadecyl silica with 100 mM phosphate buffer, pH 2.1 (33), or 5 mM phosphate buffers, pH 2.1, containing hydrophobic alkyl sulfonates (30). It is thus likely that the peptide chain proper makes only a very small contribution to the retention of peptides under these conditions. Based on partition coefficient considerations, oligomers of alanine, and the other nonpolar amino acids, should show a linear dependence of log A on the number of residues. This, in fact, has been observed. For example, the plot of log A versus the number of alanine residues shows (33) a linear dependence with a uniform log A increment due to the methyl group of the aliphatic side chain (Fig. 2), i.e., the effect is additive (45a, 46a). 

Hemoglobin consists of four polypeptide chains (two a subunits and two 3 subunits), each of which carries a heme unit. Hemoglobin has more nonpolar amino acids than myoglobin. When each subunit is folded, some of these remain on the surface. The van der Waals attraction between these hydrophobic groups is what stabilizes the quaternary structure of the four subunits. 

How does the hydrophobic effect favor protein folding Some of the amino acids that make up proteins have nonpolar groups. These nonpolar amino acids have a strong tendency to associate with one another inside the interior of the folded protein. The increased entropy of water resulting from the interaction of these hydrophobic amino acids helps to compensate for the entropy losses inherent in the folding process. 

Two important features emerge from our examination of these three examples of membrane protein structure. First, the parts of the protein that interact with the hydrophobic parts of the membrane are coated with nonpolar amino acid side chains, whereas those parts that interact with the aqueous environment are much more hydrophilic. Second, the structures positioned within the membrane are quite regular and, in particular, all backbone hydrogen-bond donors and acceptors participate in hydrogen bonds. Breaking a hydrogen bond within a membrane is quite unfavorable, because little or no water is present to compete for the polar groups. 

The two classes of amino acids that exist are based on whether the R-group is hydrophobic or hydrophilic. Hydrophobic or nonpolar amino acids tend to repel the aqueous environment and are located mostly in the interior of proteins. They do not ionize or participate in the formation of hydrogen bonds. On the other hand, the hydrophilic or polar amino acids tend to interact with the aqueous environment, are usually involved in the formation of hydrogen bonds, and are usually found on the exterior surfaces of proteins or in their reactive centers. It is for this reason that certain amino acid R-groups allow enzyme reactions to occur. 

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