computer modeling in molecular biology.pdf

96 Shoshana .L Wodak, Daniel van Belle, and Martine PrPvostFigure 4-18. Thermodynamic cycle incorporating the solvation and unfolding processes. Thewater to protein transfer process (the unfolding process) is decomposed into two separatesolvation processes: gas phase to water solvation process, and gas phase to protein solvationprocess. Boxed values correspond to the differences (Ile versus Ala) in the experimentaltransfer or solution free energy values for the organic solvents, ethanol (Ethol), octanol(Octol), cyclohexane (Chx) as well as the difference in water solution free energies. The computedAd G values for the Ile --t Ala transformation are given in bold (see legend of Figure 4-16for further details).is decomposed into two separate solvation processes which use the gas phase as areference state. We see that the total free energy difference when going from the gasphase to the protein interior (Ad G,+) is significantly larger than the correspondingdifference in hydration free energies (dAG,,,). As already outlined in Section4.3.3, this indicates that hydration effects play only a minor role in the overallfree energy balance when the difference between the sidechains of Ile and Ala is considered,despite of the fact that they provide important contributions to the freeenergy of transfer of individual sidechains from water to the protein interior. It alsosuggests furthermore that important contributions to this free energy balance areprovided by effects pertaining to the native protein.The interesting question then arises of what such effects may be. In order to addressthis question it is useful to critically examine the correlation between thechanges in unfolding free energies upon mutation and small molecule transfer data.