Quantification of the hydrophobic interaction by simulations of the aggregation of small hydrophobic solutes in water

Abstract

The hydrophobic interaction, the tendency for nonpolar molecules to aggregate in solution, is a major driving force in biology. In a direct approach to the physical basis of the hydrophobic effect, nanosecond molecular dynamics simulations were performed on increasing numbers of hydrocarbon solute molecules in waterfilled boxes of different sizes. The intermittent formation of solute clusters gives a free energy that is proportional to the loss in exposed molecular surface area with a constant of proportionality of 45 ؎ 6 cal͞mol⅐Å 2 . The molecular surface area is the envelope of the solute cluster that is impenetrable by solvent and is somewhat smaller than the more traditional solvent-accessible surface area, which is the area transcribed by the radius of a solvent molecule rolled over the surface of the cluster. When we apply a factor relating molecular surface area to solvent-accessible surface area, we obtain 24 cal͞mol⅐Å 2 . Ours is the first direct calculation, to our knowledge, of the hydrophobic interaction from molecular dynamics simulations; the excellent qualitative and quantitative agreement with experiment proves that simple van der Waals interactions and atomic point-charge electrostatics account for the most important driving force in biology.T he hydrophobic effect is the most important force in stabilizing biological structures ranging from native conformations of proteins to cellular membranes. The origin of this effect has been the topic of much investigation, both experimental and theoretical. Solvent transfer experiments show that for a wide range of different hydrocarbon molecules, the hydrophobic interaction energy depends linearly on the burial of solvent accessible surface area with a constant of proportionality around 25 cal͞mol⅐Å 2 (1-4). Data from calorimetric studies indicate that around room temperature, the hydrophobic effect is primarily entropy driven (5). Both of these results indicate that the interaction must be short-range and must depend on a shell of water molecules. The entropy effect is attributed to the solute imparting additional structure to the surrounding shell waters and reducing their entropy relative to the bulk solvent (6). Unfortunately, these macroscopic studies do little to shed light on our understanding of the detailed microscopic solute-solvent interactions that drive the hydrophobic effect.Although the microscopic details cannot be distinguished by experiment, theoretical studies are ideal for modeling atomiclevel interactions, and a great deal of our understanding of the hydrophobic effect has come from theoretical studies. Classically, there are two aspects to the hydrophobic effect. The first is termed hydrophobic hydration and concerns the effects of the solute on the surrounding water molecules. The second aspect is often referred to as the hydrophobic interaction, the tendency for nonpolar molecules to associate in water. This second aspect is the focus of the present study.A common theoretical treatment of the hydrophobic interaction has been to s...

Weak Interactions in Protein Folding: Hydrophobic Free Energy, van der Waals Interactions, Peptide Hydrogen Bonds, and Peptide Solvation

“…The simulations of cluster formation yield a proportionality between transfer free energy and burial of nonpolar surface area that is similar to the one found from liquid-liquid transfer experiments [48]. The simulation results make the important point that a standard molecular force field is able to simulate the thermodynamics of hydrophobic free energy when a hydrophobic cluster is formed in water [48]. Rank and Baker [49] found that solvent-separated hydrocarbon clusters precede the desolvated clusters found in the interior of large hydrocarbon clusters.…”

“…The gain in negative free energy from adding a hydrocarbon molecule to a hydrocarbon cluster in water increases with the size of the cluster until limiting behavior is reached for large clusters. The simulations of cluster formation yield a proportionality between transfer free energy and burial of nonpolar surface area that is similar to the one found from liquid-liquid transfer experiments [48]. The simulation results make the important point that a standard molecular force field is able to simulate the thermodynamics of hydrophobic free energy when a hydrophobic cluster is formed in water [48].…”

“…Thus, a hydrocarbon desolvation barrier may be important in the kinetics of protein folding [49]. In both simulation studies [48,49], the authors find that the molecular surface area (defined by Richards [50]) is more useful than water-accessible surface area in analyzing cluster formation.…”

“…Benzene dimers or complexes between benzene and phenol in water are barely detectable [47]. Raschke, Tsai and Levitt used molecular dynamics to simulate the formation of hydrophobic clusters, starting from a collection of isolated hydrocarbon molecules in water [48]. Their results give an interesting picture of the thermodynamics of the process.…”

The new view of hydrophobic free energy

“…A connection between hydrophobic hydration and the pairwise hydrophobic interaction was found in 2001 by Raschke, Tsai and Levitt [40], who simulated the formation of contact clusters of hydrocarbon molecules in water and compared the results with the decrease in net ASA. When several hydrocarbon molecules are placed in a box of water molecules for a simulation study, the hydrocarbon contact clusters that are formed during simulation satisfy standard tests for being equilibrium clusters [40].…”