Protein folding, apolar side chains

The van der Waals model of monomeric insulin (1) once again shows the wedge-shaped tertiary structure formed by the two chains together. In the second model (3, bottom), the side chains of polar amino acids are shown in blue, while apolar residues are yellow or pink. This model emphasizes the importance of the hydrophobic effect for protein folding (see p. 74). In insulin as well, most hydrophobic side chains are located on the inside of the molecule, while the hydrophilic residues are located on the surface. Apparently in contradiction to this rule, several apolar side chains (pink) are found on the surface. However, all of these residues are involved in hydrophobic interactions that stabilize the dimeric and hexameric forms of insulin. 

The same type of entropic effect plays a major role in directing the folding of globular proteins. About half of the amino acid side chains in proteins are hydrophobic (e.g., alanine, valine, isoleucine, leucine, and phenylalanine). Entropic effects strongly favor internal locations for these side chains where they are free from contacts with water (e.g., see fig. 1.12, which shows the location of polar and apolar side chains in cytochrome c). 

If H - H bonds widely occiu in biomolecules one may speculate what their full meaning is, in terms of the locahsation of molecular stabUity. Should the view of apolar side chains merely causing steric steering in protein folding be revised, and be replaced by one in which hydrocarbon fragments display as of yet unappreciated relationships of attraction QCT could also be instrumental in explaining frequently imexpected fragmentation patterns in peptide mass spectrometry. 

Fig. 10. Schematic conformation of sperm whale myoglobin after Kendtew et al. (48). The sausage is the protein chain, which is mostly in the a-hdical conformation. The heme group is held in a cleft by apolar contacts, and by two histidine side chmns. Three or four other histidine side chains participate in the fcxmaticm the folded protein structure. Since the side chain of histidine contains an imidazole ring, a free side chain can be protonated at low pH (the pK is ca. 6.5). However, the five or six buried side chains cannot be protonated, and hence the overall equilibrium constant for unfolding is strongly pH dependent in first approximation (34)...

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