Solvent accessible surface area of amino acid residues in globular proteins: correlation of apparent transfer free energies with experimental hydrophobicity scales.

It is known that the distribution of amino acid residues in globular proteins between surface and interior is in certain correlation with various experimental scales based on partitioning of amino acids or their analogs between water and organic solvents. These scales are often used in various quantitative structure-activity relationship (QSAR) studies as well as for evaluation of stability of proteins. In this work we have analyzed the distribution of residues based on their solvent accessible surface area in more than 8000 protein structures. Using extensive statistical sampling, we have computed residue apparent free energies of transfer between protein interior and surface applying various criteria for classifying residues as exposed or buried. The correlation of these statistical energies with several experimental hydrophobicity scales is discussed. We propose three types of statistical apparent transfer free energy scales and show that each of these scales is in better correlation with one of the experimental hydrophobicity scales (water/vapor, water/cyclohexane, and water/octanol transfer scales). The data are interpreted through the application of theoretical considerations by Finkelstein et al. (Protein Struct. Funct. Genet. 1995, 23, 142) based on random energy model of heteropolymer globules. The deviation of apparent transfer free energies from experimental scales is discussed and analyzed. The variations of amino acid distribution in proteins with the size of protein structure is discussed and the final protein set is chosen to minimize these variations.