Figure 1. Molecular origins of hydrophobicity. Typical hydrogen bonding (dashed lines) pattern among water molecules H₂O: (a) in the bulk; (b) around a small nonpolar solute (shaded circle); and (c) near an extended nonpolar surface. The hydrogen bonding geometry in (b) is distorted relative to that in (a) to maintain an interaction strength among water molecules comparable to that in the bulk. Water molecules around a small solute with a convex nonpolar surface are oriented to avoid directing their hydrogen-bonding groups (donor or acceptor) towards the solute. This arrangement is not possible near a flat extended nonpolar surface. In this case there are ‘dangling’ hydrogen bonds, i.e. potentially hydrogen-bonding groups (dotted lines) oriented towards the nonpolar surface (Lee et al., 1984).

Figure 2. Experimental and statistical procedures for estimating amino acid interaction parameters. (a) Formation of a contact when a biomolecule undergoes conformational changes, as in protein folding. The aqueous solvent is not depicted explicitly. (b) Modelling contact formation by transferring a model compound (small solute) from an aqueous phase (left) to a nonpolar phase (right). Hydrophobic hydration is also studied by transferring small solutes from a gaseous phase (middle) to water. (c) Modelling contact formation by studying the partitioning of solutes into aligned nonpolar phases such as bilayers and in reversed-phase liquid chromatography experiments. (d) Some interaction parameters are deduced from the statistics of contacts among different amino acid types in the database of protein native structures.

Figure 3. Hydrophobicity scales obtained from different techniques and their applications to protein folding. (a) Correlation between the reversed-phase liquid chromatography (RPLC) scale in Table 1 (a) and one of the Wimley, Creamer and White (1996) scales (red dots), the scale of Fauchère and Pliška (1983) (blue dots, Table 1 (b)), and that of Wimley and White (1996) (green dots, Table 1 (c)). Least square fits are given by the upper and lower solid lines and the dashed line, with correlation coefficient r = 0.96, 0.87 and 0.72, respectively; see DeVido et al. (1998) in Table 2 for details. (b) A set of 210 interaction parameters between pairs of amino acids determined statistically from a database of protein native structures (Miyazawa and Jernigan, 1996) are plotted against pairwise sums of hydrophobicities (Fauchère and Pliška, 1983) of the corresponding amino acids; solid line is the least square fit, r = 0.90. (c) G_fold is the folding free-energy change caused by the type of single-site mutation given below the horizontal axis. A larger G_fold means that the mutation results in a less stable native structure. A total of 48 different experimental values of G_fold are plotted (open circles). The same mutation can produce very different changes in folding free energy in different proteins or at different sites of the same protein. The ranges of corresponding free-energy changes predicted by small model compound results and the analysis of Lee are indicated by the dashed boxes. Part (c) of this figure is adapted from Lee (1993); more details are given in this reference.