The hydrophobic effect[1-3] between solutes in aqueous solutions plays a central role in our understanding of recognition and folding of proteins[4, 5], and association of lipids [6,7]. This effect has recently been restudied and new mechanisms proposed for its origins . Central to the debate is whether dewetting of the hydrophobic surfaces occurs prior to contact or at distances where water would not be allowed to intervene sterically . Small hydrophobic solutes have been well studied [9-15]. The mechanism by which small solutes are accomodated into the natural cavities of water within the hydrogen bond network is well understood. Solvation of a large hydrophobic solute in water is thought to be associated with an energy cost due to partial disruption of hydrogen bond networks . This mechanism leads to dewetting for specific cases and thus a particular mechanism for the hydrophobic effect. The question then is whether there are other energetic compensations which dictate a differing mechanism. The energetic imbalance required for dewetting would be maximal when considering a purely repulsive model for nonpolar solutes in water where in- complete hydrogen bonding might occur near such a repulsive solute with a large radius of curvature. Low dimensional networks of water might not be expected to have sufficient cohesion to be stable near such solutes. The imbalance in forces would cause an effective potential-cavity expulsion potential(CEP) to be generated. The effect of the CEP should increase with increasing size of the solute due to an increasing interfacial region. For a large solute of nanometer size and above the CEP causes water to be pushed away from the solute surface forming a thin vapor layer around it in this picture[17, 8]. When two such solutes come closer to each other the fluctuations in the vapor-liquid interface between the individual solutes aids in growing the vapor layer and finally creating a vacuous or dewetted region between the two solutes. Once the intersolute region is a vacuum the solutes would then aggregate due to the solvent induced forces on them. This theoretical picture of hydrophobic dewetting induced collapse [8,18-20] has been supported by simulations [22-25] using purely repulsive or weakly attractive solute potentials. Theoretical works by Chandler and coworkers [8,18-20] based on a mesoscopic square gradient theory for the liquid-vapor interface imply that hydration behavior interpolates between the traditional view of a small hydrophobic solute to this quite different picture for a large hydrophobic solute for such models. The results from a series of investigations[28, 29] from our Laboratory clearly demonstrate the importance of the weak dispersion interactions naturally present in essentially all nonpolar substances to study hydration behavior of such solutes in general and dewetting in the intersolute region in particular. Our results indicate that the dewetting induced collapse of large hydrophobic solutes as predicted by many recent investigations [8,18, 21, 23, 24] based on either purely repulsive or weakly attractive solute potential may not apply to hydrophobic solutes like protein interfaces which have significant polarity and dispersion interactions. These results should be considered when interpreting the mechanism of aggregation phenomena observed in many areas of chemistry and biology.
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