HYDROPHOBIC HYDRATION, HYDROPHOBIC FORCES AND PROTEIN-FOLDING

There is no general agreement about the molecular mechanism of hydroph obic hydration. The preferred models all consider only the state of si ngle water molecules immediately adjacent to the hydrophobic solute to which they cannot hydrogen bond. Because, fortuitously, all experimen ts, until recently, have been done at room temperature, the large decr ease in entropy accompanying hydrophobic hydration has been taken to m ean that the phenomenon is ''entropy driven'' when common sense says t hat the effect of losing a whole hydrogen bond is a large increase in enthalpy. At higher temperatures, enthalpy does become positive, furth er confusing interpretation. When the cooperativity of water-water hyd rogen bonding is taken into account, many of the conceptual difficulti es of the nature of hydrophobic hydration, the magnitude of the hydrop hobic force and its role in protein folding disappear. (1) It accounts for the long-range over which the hydrophobic force can sometimes (bu t not always) act. (2) It suggests that an appreciable population of w ater molecules close to a hydrophobic surface, out-of-equilibrium with more distant populations compensate for their excess enthalpy by expa nding and decreasing their local chemical potential. This explains the thermodynamic findings for transfer of hydrocarbons from the vapour p hase to water as a function of temperature. (3) It offers a resolution of the current uncertainty as to whether the hydrophobic interaction stabilises or destabilises the folded conformation of proteins. The be lief that it is destabilising is based on extensive calorimetric measu rements 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 prot ein to contact with water. It is suggested that this is an inappropria te model. (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 incompatibili ty. Low-density water, which has stronger hydrogen bonds and lower int rinsic entropy than normal water has been shown to form outside double layers of polyelectrolytes. This low-density water can overlap adjace nt nonpolar amino acids, inducing a powerful driving force for their s equestration out of contact with low-density water. (5) It offers mech anisms for the effects of ions of the Hofmeister series and of compens atory solutes in the stabilisation and destabilisation of folded prote ins and ether structures. (6) Other biological structures such as mice lles, lipid bilayers, polysaccharides and polynucleotides also have bo th hydrophobic and charged groups to generate the extreme oil/low-dens ity water incompatibility which promotes structures of singular stabil ity and order.