Amino Acid Side‐chain Hydrophobicity


Hydrophobicity is the unfavourable energetics of dissolving nonpolar compounds in water. The hydrophobicities of the 20 amino acid side‐chains are currently described by hydrophobicity scales derived primarily from solubility studies; these scales have provided semiquantitative rationalizations of some properties of native (folded) proteins.

Keywords: model compounds; solvation; statistical potentials

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., ).

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 (a) and one of the Wimley, Creamer and White scales (red dots), the scale of Fauchère and Pliška (blue dots, Table (b)), and that of Wimley and White (green dots, Table (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. in Table 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, ) are plotted against pairwise sums of hydrophobicities (Fauchère and Pliška, ) of the corresponding amino acids; solid line is the least square fit, r = 0.90. (c) ΔΔGfold is the folding free‐energy change caused by the type of single‐site mutation given below the horizontal axis. A larger ΔΔGfold means that the mutation results in a less stable native structure. A total of 48 different experimental values of ΔΔGfold 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 ; more details are given in this reference.



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Further Reading

Cheng Y‐K and Rossky PJ (1998) Surface topography dependence of biomolecular hydrophobic hydration. Nature 392: 696–699.

Dill KA (1990) Dominant forces in protein folding. Biochemistry 29: 7133–7155.

Hummer G, Garde S, Garcia AE, Paulaitis ME and Pratt LR (1998) Hydrophobic effects on a molecular scale. Journal of Physical Chemistry B 102: 10469–10482.

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Liu L‐P and Deber CM (1998) Uncoupling hydrophobicity and helicity in transmembrane segments: α‐helical propensities of the amino acids in non‐polar environments. Journal of Biological Chemistry 273: 23645–23648.

Park BH, Huang ES and Levitt M (1997) Factors affecting the ability of energy functions to discriminate correct from incorrect folds. Journal of Molecular Biology 266: 831–846.

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Robertson AD and Murphy KP (1997) Protein structure and the energetics of protein stability. Chemical Reviews 97: 1251–1267.

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Skolnick J, Jaroszewski L, Kolinski A and Godzik A (1997) Derivation and testing of pair potentials for protein folding. When is the quasichemical approximation correct? Protein Science 6: 676–688.

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Chan, Hue Sun(Mar 2002) Amino Acid Side‐chain Hydrophobicity. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0003005]