Hydrophobic hydration, hydrophobic forces and protein folding

There is no general agreement about the molecular mechanism of hydrophobic hydration. The preferred models all consider only the state of single water molecules immediately adjacent to the hydrophobic solute to which they cannot hydrogen bond. Because, fortuitously, all experiments, until recently, have been done at room temperature, the large decrease in entropy accompanying hydrophobic hydration has been taken to mean that the phenomenon is “entropy driven” when common sense says that the effect of losing a whole hydrogen bond is a large increase in enthalpy. At higher temperatures, enthalpy does become positive, further confusing interpretation. When the cooperativity of water-water hydrogen bonding is taken into account, many of the conceptual difficulties of the nature of hydrophobic hydration, the magnitude of the hydrophobic force and its role in protein folding disappear. 1. (1) It accounts for the long-range over which the hydrophobic force can sometimes (but not always) act. 2. (2) It suggests that an appreciable population of water molecules close to a hydrophobic surface, out-of-equilibrium with more distant populations compensate for their excess enthalpy by expanding and decreasing their local chemical potential. This explains the thermodynamics findings for transfer of hydrocarbons from the vapour phase to water as a function of temperature. 3. (3) It offers a resolution of the current uncertainty as to whether the hydrophobic interaction stabilises or destabilises the folded conformation of proteins. The belief that it is destabilising is based on extensive calorimetric measurements of transfer of amino acids from the vapour phase to water as a model for the transfer of amino acids from the central core of a protein to contact with water. It is suggested that this is an inappropriate model. 4. (4) It is shown that the true hydrophobic interaction which drives protein folding is not due to oil/water incompatibility as has always been assumed, but is due to oil/low-density water incompatibility. Low-density water, which has stronger hydrogen bonds and lower intrinsic entropy than normal water has been shown to form outside double layers of polyelectrolytes. This low-density water can overlap adjacent nonpolar amino acids, inducing a powerful driving force for their sequestration out of contact with low-density water. 5. (5) It offers mechanisms for the effects of ions of the Hofmeister series and of compensatory solutes in the stabilisation and destabilisation of folded proteins and other structures. 6. (6) Other biological structures such as micelles, lipid bilayers, polysaccharides and polynucleotides also have both hydrophobic and charged groups to generate the extreme oil/low-density water incompatibility which promotes structures of singular stability. and order