Excluded volume in solvation: Sensitivity of scaled-particle theory to solvent size and density

Changes in solvent environment greatly affect macromolecular structure and stability. To investigate the role of excluded volume in solvation, scaled-particle theory is often used to calculate DeltaG(tr)(ev), the excluded-volume portion of the solute transfer free energy, DeltaG(tr). The inputs to SPT are the solvent radii and molarities. Real molecules are not spheres. Hence, molecular radii are not uniquely defined and vary for any given species. Since DeltaG(tr)(ev) is extremely sensitive to solvent radii, uncertainty in these radii causes a large uncertainty in DeltaG(tr)(ev)-several kcal/mol for amino acid solutes transferring from water to aqueous mixtures. This uncertainty is larger than the experimental DeltaG(tr) values. Also, DeltaG(tr)(ev) can be either positive or negative. Adding neutral crowding molecules may not necessarily reduce solubility. Lastly, DeltaG(tr)(ev) is very sensitive to solvent density, rho. A few percent error in rho may even cause qualitative deviations in DeltaG(tr)(ev). For example, if rho is calculated by assuming the hard-sphere pressure to be constant, then DeltaG(tr)(ev) values and uncertainties are now only tenths of a kcal/mol and are positive. Because DeltaG(tr)(ev) values calculated by scaled-particle theory are strongly sensitive to solvent radii and densities, determining the excluded-volume contribution to transfer free energies using SPT may be problematic.