Hydrophobic effect

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A droplet of water forms a spherical shape, minimizing contact with the hydrophobic leaf.

The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in aqueous solution and exclude water molecules,[1][2] and they fall, specifically under the title rubric when a particular temperature dependence of the affinity of the apolar small molecule or moiety for the aqueous phase obtains.[citation needed] The part of the name, hydrophobic, literally meaning "water-fearing," and it describes the segregation and apparent repulsion between water and nonpolar substances.

The hydrophobic effect explains the separation of a mixture of oil and water into its two components, and the beading of water on nonpolar surfaces such as waxy leaves. At the molecular level, the hydrophobic effect is important in driving protein folding,[3][4] formation of lipid bilayers and micelles, insertion of membrane proteins into the nonpolar lipid environment and protein-small molecule interactions.[5][6] Substances for which this effect is observed are known as hydrophobes.


Amphiphiles are molecules that have both hydrophobic and hydrophilic domains. Detergents are composed of amphiphiles that allow hydrophobic molecules to be solubilized in water by forming micelles and bilayers (as in soap bubbles). They are also important to cell membranes composed of amphiphilic phospholipids that prevent the internal aqueous environment of a cell from mixing with external water.

Folding of macromolecules[edit]

In the case of protein folding, the hydrophobic effect is important to understand the structure of proteins that have hydrophobic amino acids, such as alanine, valine, leucine, isoleucine, phenylalanine, tryptophan and methionine clustered together within the protein. Structures of water-soluble proteins have a hydrophobic core in which side chains are buried from water, which stabilizes the folded state, and charged and polar side chains are situated on the solvent-exposed surface where they interact with surrounding water molecules. Minimizing the number of hydrophobic side chains exposed to water is the principal driving force behind the folding process,[7] although formation of hydrogen bonds within the protein also stabilizes protein structure.[8]

The energetics of DNA tertiary structure assembly were determined to be driven by the hydrophobic effect, in addition to Watson-Crick base pairing (which is responsible for sequence selectivity) and a significant contribution from stacking interactions between the aromatic bases.[9][10]

Protein purification[edit]

In biochemistry, the hydrophobic effect can be used to separate mixtures of proteins based on their hydrophobicity. Column chromatography with a hydrophobic stationary phase such as phenyl-sepharose will cause more hydrophobic proteins to travel more slowly, while less hydrophobic ones elute from the column sooner. To achieve better separation, a salt may be added (higher concentrations of salt increase the hydrophobic effect) and its concentration decreased as the separation goes on.

The origin of hydrophobic effect[edit]

Dynamic hydrogen bonds between molecules of liquid water

The origin of the hydrophobic effect is not fully understood. Some argue that the hydrophobic interaction is mostly an entropic effect originating from the disruption of highly dynamic hydrogen bonds between molecules of liquid water by the nonpolar solute.[11] A hydrocarbon chain or a similar nonpolar region or a big molecule is incapable of forming hydrogen bonds with water. Introduction of such a non-hydrogen bonding surface into water causes disruption of the hydrogen bonding network between water molecules. The hydrogen bonds are reoriented tangentially to such surface to minimize disruption of the hydrogen bonded 3D network of water molecules and thus leads to a structured water "cage" around the nonpolar surface. The water molecules that form the "cage" (or solvation shell) have restricted mobilities. In the solvation shell of small nonpolar particles, the restriction amounts to some 10%, e.g. in the case of dissolved Xe at room temperature, a mobility restriction of 30% has been found.[12] In the case of larger nonpolar molecules the reorientational and translational motion of the water molecules in the solvation shell may be restricted by a factor of two to four. Thus at 25°C the reorientational correlation time of water increases from 2 to 4-8 picoseconds. Generally, this leads to significant losses in translational and rotational entropy of water molecules and makes the process unfavorable in terms of free energy of the system.[13] By aggregating together, nonpolar molecules reduce the surface area exposed to water and minimize their disruptive effect.

The hydrophobic effect can be quantified by measuring the partition coefficients of non-polar molecules between water and non-polar solvents. The partition coefficients can be transformed to free energy of transfer which includes enthalpic and entropic components, ΔG = ΔH - TΔS. These components are experimentally determined by calorimetry. The hydrophobic effect was found to be entropy-driven at room temperature because of the reduced mobility of water molecules in solvation shell of the non-polar solute. However, the enthalpic component of transfer energy was found to be favorable, meaning strengthening of water-water hydrogen bonds in the solvation shell, apparently due to the reduced mobility of water molecules. At the higher temperature, when water molecules became more mobile, this energy gain decreases, but so does the entropic component. The hydrophobic effect increases with temperature, which leads to "cold denaturation" of proteins.[14]

See also[edit]


  1. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "hydrophobic interaction".
  2. ^ Interfaces and the driving force of hydrophobic assembly Nature, Volume 437, Issue 7059, pp. 640-647 (2005)doi:10.1038/nature04162
  3. ^ Kauzmann W (1959). "Some factors in the interpretation of protein denaturation". Advances in Protein Chemistry 14: 1–63. doi:10.1016/S0065-3233(08)60608-7. PMID 14404936. 
  4. ^ Charton, M.; Charton, B. I. (1982). "The structural dependence of amino acid hydrophobicity parameters". Journal of Theoretical Biology 99 (4): 629–644. doi:10.1016/0022-5193(82)90191-6. PMID 7183857.  edit
  5. ^ "The Binding of Benzoarylsulfonamide Ligands to Human Carbonic Anhydrase is Insensitive to Formal Fluorination of the Ligand" Angew. Chem., Int. Ed., Volume 52, Issue 30, pp. 7714-7717 2003; DOI: 10.1002/anie.201301813
  6. ^ "Water Networks Contribute to Enthalpy/Entropy Compensation in Protein–Ligand Binding" J. Am. Chem. Soc., 2013, 135 (41), pp 15579–15584; DOI: 10.1021/ja4075776
  7. ^ Pace C, Shirley B, McNutt M, Gajiwala K (1 January 1996). "Forces contributing to the conformational stability of proteins". FASEB J. 10 (1): 75–83. PMID 8566551. 
  8. ^ Rose G, Fleming P, Banavar J, Maritan A (2006). "A backbone-based theory of protein folding". Proc. Natl. Acad. Sci. U.S.A. 103 (45): 16623–33. doi:10.1073/pnas.0606843103. PMC 1636505. PMID 17075053. 
  9. ^ Gilbert, H.F. (2000) Basic Concepts in Biochemistry - A Student's Survival Guide (2nd Edition). McGraw-Hill page 9.
  10. ^ van Holde K.E., Johnson W.C. and Ho P.S. Principles of Physical Biochemistry (Prentice-Hall 1998) page 18. See also thermodynamic discussion pages 137-144.
  11. ^ The Real Reason Why Oil and Water Don't Mix Todd P. Silverstein, J. Chem. Educ. 1998, 75 (1), p 116
  12. ^ Haselmeier, R.; Holz, M.; Marbach, W.; Weingaertner, H. (1995). "Water Dynamics near a Dissolved Noble Gas. First Direct Experimental Evidence for a Retardation Effect". The Journal of Physical Chemistry 99 (8): 2243. doi:10.1021/j100008a001.  edit
  13. ^ Charles Tanford (1973). The Hydrophobic Effect: Formation of Micelles and Biological Membranes. New York, NY: John Wiley & Sons Inc. ISBN 978-0-471-84460-0.
  14. ^ Jaremko, M., Jaremko, L., Kim, H.-Y., Cho, M.-K., Schwieters, C. D., Giller, K., Becker, S., Zweckstetter, M. (2013) Cold denaturation of a protein dimer monitored at atomic resolution, Nat. Chem. Biol. 9, 264-270.

Further reading[edit]