APPLICATION OF SCALED PARTICLE THEORY TO MODEL THE HYDROPHOBIC EFFECT- IMPLICATIONS FOR MOLECULAR ASSOCIATION AND PROTEIN STABILITY

The energetics of alkane dissolution and partition between water and o rganic solvent are described in terms of the energy of cavity formatio n and solute-solvent interaction using scaled particle theory. Thermod ynamic arguments are proposed that allow comparison of experimental me asurements of the surface area with values calculated from an all-atom representation of the solute. While the surface tension relating to t he accessible surface is shape dependent, it is found that for the mol ecular surface it is not. This model rationalizes the change in surfac e tension between the microscopic (20-30 cal/mol/Angstrom(2)) and macr oscopic (70-75 cal/mol/Angstrom(2)) regimes without the need to invoke Flory-Huggins theory or to apply other corrections. The difference in the values arises (i) to a small extent as a result of the curvature dependence of surface tension and (ii) to a large extent due to the di fference in the molecular surface derived from the experiment and that calculated from an extended all-atom model. The model suggests that t he primary driving force for alkane association in water is due to the tendency of water to reduce the solute cavity surface. It is argued t hat to model the energetics of alkane association, the surface tension should be related to the molecular surface (rather than the accessibl e surface) with a surface tension near the macroscopic limit for water . This model is compared with results from theoretical simulations of the hydrophobic effect for two well-studied systems. The implications for antibody-antigen interactions and the effect of hydrophobic amino acid deletion on protein stability are discussed. The approach can be used to model the solute cavity formation energy in solution as a firs t step in the continuum modelling of biomolecular interactions.