Excluded Volume in Solvation: Sensitivity of Scaled-Particle Theory to Solvent Size and Density

AbstractChanges 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 ΔGtrev, the excluded-volume portion of the solute transfer free energy, ΔGtr. 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 ΔGtrev is extremely sensitive to solvent radii, uncertainty in these radii causes a large uncertainty in ΔGtrev—several kcal/mol for amino acid solutes transferring from water to aqueous mixtures. This uncertainty is larger than the experimental ΔGtr values. Also, ΔGtrev can be either positive or negative. Adding neutral crowding molecules may not necessarily reduce solubility. Lastly, ΔGtrev is very sensitive to solvent density, ρ. A few percent error in ρ may even cause qualitative deviations in ΔGtrev. For example, if ρ is calculated by assuming the hard-sphere pressure to be constant, then ΔGtrev values and uncertainties are now only tenths of a kcal/mol and are positive. Because ΔGtrev 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