Hydrophobicity regained

Abstract

A widespread practice is to use free energies of transfer between organic solvents and water (AGEansfer) to define hydrophobicity scales for the amino acid side chains. A comparison of four AGEansfer scales reveals that the values for hydrogen-bonding side chains are highly dependent on the non-aqueous environment. This property of polar side chains violates the assumptions underlying the paradigm of equating AGEansfer with hydrophobicity or even with a generic solvation energy that is directly relevant to protein stability and ligand binding energetics. This simple regaining of the original concept of hydrophobicity reveals a flaw in approaches that use AGEansfer values to derive generic estimates of the energetics of the burial of polar groups, and allows the introduction of a "pure" hydrophobicity scale for the amino acid residues.Keywords: amino acids; atomic solvation parameters; hydrophobic effect; hydrophobicity; protein folding; protein stabilityThe hydrophobic effect describes the thermodynamics of the partitioning of non-polar compounds between water and a nonaqueous phase. The hallmarks of the hydrophobic effect are that the transfer of non-polar compounds into water at ambient temperature is unfavorable due to a decrease in entropy and is associated with a large increase in heat capacity. Although the molecular details that give rise to the hydrophobic effect are still debated (Blokzijl & Engberts, 1993), this has not hindered it from becoming the dominant paradigm for understanding protein folding and stability (e.g

Structural and Kinetic Effects on Changes in the CO2 Binding Pocket of Human Carbonic Anhydrase II

“…This is associated with a 13- to 17-fold decrease in k cat /K m and k cat ex /K eff CO2 for hydration when V143I is compared with wild type (Tables 2, 3). This sterically crowded active site due to the increased volume of Ile143 is accompanied by the effects of increased hydrophobicity of Ile143 compared with Val143 (estimated at 0.5 kcal/mol based on side chain burial (25)). The overall effect on V143I HCA II is to increase an apparent energy barrier by about 1.7 kcal/mol for catalysis that in wild-type is near 10 kcal/mol.…”

The intrinsic disorder alphabet. III. Dual personality of serine

“…Serine residue has a non-polar surface of 56 A 2 , and the estimated hydrophobic effect associated with the burial of this residue is 1.40 kcal/mol, whereas the estimated hydrophobic effect associated with the burial of side chain of this residue is 0.2 kcal/mol. 51 In ordered proteins, serine residues are predominantly located on protein surface so that they have access to the solvent. In fact, 70% (375 of 533) of serine residues in analyzed structures of 9 folded proteins are classified as exposed since they have solvent exposed areas of >30 A 2 , and 30% of serines in folded proteins possess solvent exposed areas of <10 A 2 and therefore are buried.…”

Mutagenesis of a Specificity-Determining Residue in Tyrosine Hydroxylase Establishes That the Enzyme Is a Robust Phenylalanine Hydroxylase but a Fragile Tyrosine Hydroxylase

“…For the K m and V max /K m values with either tyrosine or phenylalanine as substrate, there is no significant correlation with the volume(35, 36), accessible surface area(37), or any of several measures of the hydrophobicity(38–42) of the individual residues (results not shown). In contrast, there is a strong negative correlation between the V max value for tyrosine hydroxylation and the hydrophobicity of the amino acid residue at position 425 (Table S1).…”

“…The substrate specificity of the different variants, as reflected in the ratio of the V max /K tyr value to the V max /K phe value, shows a weak negative correlation with the hydrophobicity of the residue, with an R 2 value of 0.40 versus the energy of transfer from cyclohexane to water when the charged residues are not included and an R 2 value of 0.27 versus the estimated hydrophobic effect for side chain burial from Karplus(42) when charged residues are considered (Table S1). The wild-type enzyme has the highest specificity for tyrosine over phenylalanine, while TyrH D425V has the highest specificity for phenylalanine over tyrosine.…”

“…A large number of hydrophobicity scales for amino acid residues have been developed over the years, primarily to gain insight into the contribution of hydrophobic interactions to protein folding(55, 56). The accuracy with which any specific hydrophobicity scale predicts the effects of site-directed mutagenesis on protein structure is clearly context dependent, and charged and polar amino acid side chains are capable of other than hydrophobic interactions(42). In light of these complications, we did not attempt to determine the hydrophobicity scale that gave the best fit to the data from the many available scales, but instead focused on a representative selection of hydrophobicity scales and other properties of amino acid side chains.…”