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

The hydrophobic interaction, the tendency for nonpolar molecules to aggrega te in solution, is a major driving force in biology. In a direct approach t o the physical basis of the hydrophobic effect, nanosecond molecular dynami cs simulations were performed on increasing numbers of hydrocarbon solute m olecules in water-filled boxes of different sizes. The intermittent formati on 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 cal/mol . Angstrom (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 ar ea 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 s olvent-accessible surface area, we obtain 24 cal/mol . Angstrom (2). Ours i s the first direct calculation, to our knowledge, of the hydrophobic intera ction from molecular dynamics simulations; the excellent qualitative and qu antitative agreement with experiment proves that simple van der Waals inter actions and atomic point-charge electrostatics account for the most importa nt driving force in biology.