Stability, hydrophobic free energy

The hydrophobic free energy contribution to the stability of protein-protein complexes can also be estimated making similar assumptions to the ones described above (9). In this case as well (Table V) it appears that hydrophobic interactions contribute greatly to the overall stability of the complexes. This is particularly interesting in the case of the trypsin-pancreatic trypsin inhibitor complex since very few residues are involved in the interaction of the two molecules. 

Table IV. Hydrophobic Free Energy Contribution to Protein Stability (5)...

Reduction in the area of exposed hydrophobic surfaces can also enhance thermodynamic stability. Chothia has estimated a proportionality constant of 24 cal/ mol of hydrophobic free energy per square angstrom of solvent-exposed surface area (32). Substitutions at Ile-3 of T4 lysozyme enhance the stability by amounts that agree surprisingly well with this prediction (33). However, there is some debate over the choice of the proper hydrophobicity scale to quantitate the contributions of each hydrophobic residue, and it is perhaps an oversimplification to expect such a simple relationship to hold for all amino acids (34). 

Equation (5.15) brings li t to certain semi-quantitative aspects of initiator efficiency. PCX entry into itxiically stabilized particles, it has been shown that an estimate of the value of z can be obtained fKxn hydrophobic free energy considerations [21], yielding ... 

Several different kinds of noncovalent interactions are of vital importance in protein structure. Hydrogen bonds, hydrophobic interactions, electrostatic bonds, and van der Waals forces are all noncovalent in nature, yet are extremely important influences on protein conformations. The stabilization free energies afforded by each of these interactions may be highly dependent on the local environment within the protein, but certain generalizations can still be made. 

Errors of this magnitude make the useful prediction of free energies a difficult task, when differences of only one to three kcal/mol are involved. Nevertheless, within the error limits of the computed free energy differences, the trend is that relative to 8-methyl-N5-deazapterin or 8-methyl-pterin, the compounds methyl substituted in the 5, 6 or 7 positions are thermodynamically more stable when bound to DHFR largely by virtue of a hydrophobic effect, i.e. methyl substitution reduces the affinity of the ligand for the solvent more than it reduces affinity for the DHFR active-site. The stability of ligand binding to DHFR appears to be optimal with a 6-methyl substituent additional 5-methyl and/or 7-methyl substitution has little effect... 

Rejto, P. A., Verkhivker, G. M. (1998) Molecular anchors with large stability gaps ensure linear binding free energy relationships for hydrophobic substituents. Pacific Symp Biocomput 1998, 362-373. 

Why denaturants such as urea and GdmCl cause proteins to denature may be considered empirically. Those denaturants solubilize all the constituent parts of a protein, from its polypeptide backbone to its hydrophobic side chains. To a first approximation, the free energy of transfer of the side chains and polypeptide backbone from water to solutions of denaturant is linearly proportional to the concentration of denaturant.7,8 Because the denatured state is more exposed to solvent than the native state, the denatured state is preferentially stabilized by denaturant. Thus, the free energy of denaturation at any particular concentration of denaturant is given by... 

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