Intramolecular hydrophobic interactions

Ben-Naim, A., Wiff, J. (1979) A direct measurement of intramolecular hydrophobic interactions. J. Chem. Phys. 70, 771-777. 

A number of different molecular mechanisms can underpin the loss of biological activity of any protein. These include both covalent and non-covalent modification of the protein molecule, as summarized in Table 6.5. Protein denaturation, for example, entails a partial or complete alteration of the protein s three-dimensional shape. This is underlined by the disruption of the intramolecular forces that stabilize a protein s native conformation, namely hydrogen bonding, ionic attractions and hydrophobic interactions (Chapter 2). Covalent modifications of protein structure that can adversely affect its biological activity are summarized below. 

Frank et al. [29] studied the effect of hydrophobic interaction by comparing the fluorescent properties of PMAA/PEO and with those of PAA/PEO . Here PEO denotes pyrene end-labeled PEO. Figure 3 shows the intensity ratio le/Im of inframolecular excimer pyrene for PMAA/PEO (9200) and PAA/PEO (9200). It is seen that when added, PMAA more markedly reduces intramolecular excimer formation in PEO than does PAA. This difference is thought to be due to a stronger abihty of PMAA to combine PEO and the consequent suppression of intramolecular cychzation of PEO. 

Retro-Diels-Alder reactions of anthracenedione (51a) have been shown to proceed faster in aqueous solution than in organic solvents, apparently as a consequence of enhanced hydrogen bonding of water to the activated complex,30 since hydrophobic interactions with (51a) are of negligible importance. The results have been compared with previous kinetic data for bimolecular and intramolecular Diels-Alder reactions and the corresponding hydrogen bond and hydrophobic interactions have been discussed. 

A more extensive study of mobilities of 3H- and 14C-labeled amino acids again found that amino acids labeled with 14C at Cl or C2 are retained on the column, relative to the unlabeled forms.135 Lysine is an exception. Tritiation at C3 also increases the retention time, but tritiation at C2 of glycine or at C4, C5, or C6 of lysine decreases it, and large decreases are seen with methionine tritium-labeled in the methyl and with tyrosine tritium-labeled at C3, 5. The 14C IEs can be attributed to a decrease of acidity, but the IEs of distant 3H may be due to hydrophobic interactions with the resin. A remarkable result is that intramolecular isotopic isomers (isotopomers) can be distinguished on the basis of their chromatographic mobilities. 

Calculations [46] and studies of intramolecular oxaziridinium epoxidations [47] suggest that, like their dioxirane counterparts, these epoxidation processes proceed via spiro-transition states. However, the iminium epoxidations are generally more substrate-specific than those using dioxiranes, and models to explain the observed trends in stereocontrol have proved more difficult to construct. One complication is the possibility of formation of diastereomeric oxaziridinium salts from most of the iminium catalysts. Houk has rationalized computationally the observed enantioselectivity with Aggarwal s catalyst 16 [46]. The results of a recent study by Breslow suggest that hydrophobic interactions are important in these processes [48], and aromatic-aromatic interactions between catalyst and substrate may also play a role. 

Substrate Affinity. Enzyme-substrate affinity, as estimated by the Michaelis constant (Km), is affected also by habitat temperature (37). In many cases, the temperature range at which the Michaelis constant is minimal coincides closely with the temperature of the organism s native environment. Wiggs (43) observed that the Km of thyroid protease from burbot is lower for winter fish than for summer fish. Hofer et al. (44) also showed that the Km of trypsin from various species, including fish, correlated with the temperature preferendum of each species. The response of Km to temperature appears to relate to the balance of electrostatic and hydrophobic interactions of the active site with substrate and intramolecular bonds within the enzyme (38,39,45,46,47). 

Noncovalent interactions are weak inter- or intramolecular interactions that result from a combination of electrostatic interactions (ionic), hydrogen bonding, hydrophobic interactions (stacking or intercalation), and van der Waals interactions (dipole-dipole or induced dipole-induced dipole). Complexes formed by these types of interactions are usually fragile. This property is often essential to their biological function, which depends on the equilibria between the associated and free forms of these molecules. 

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