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of the free energy trends of electrostatics and nonpolar contributions (Choudhury
and Pettitt 2006b). We find a quite linear trend in the cavity term for relatively short
oligomers of glycine (Hu et al. 2010a). In fact, we find the small vdW attractions
compensate for the cavity
penalty
and leave a small but favorable contribution for
the completely uncharged peptide.
This is not anticipated from cavity hydrophobicity considerations of nonpolar sol-
vation. We need to use our new pictures/theories of the mechanisms to explain this,
as clearly the traditional
hydrophobicity plus electrostatics
picture is not quantita-
tively helpful in explaining the experimental data and simulations at this level.
In addition, the decomposable free energy simulation techniques we have recently
developed allow for the calculation of the solvation and transfer free energies of
model peptide solutions to be evaluated with excellent reproducibility and preci-
sion. We use a variant of replica exchange we have created (Hu et al. 2010a), which
has advantages similar to other new methods (Jiang, Hodoscek, and Roux 2009)
that allows an essentially automatic coverage of the free energy charging coordi-
nate in a thermodynamic calculation. Previous methods allowed the calculation of
chemical potentials of solvent or cosolvent with good results. This method, however,
allows the calculation for larger more complex molecular components in the system.
Adequate sampling of the fluctuations and their correlations is of critical importance
to success in these applications.
Using the new simulation methods together with a rigorous theory gives a differ-
ent picture of the landscape of protein folding with which to interpret experiment.
We find while electrostatics is important, it remains so even when explicit hydrogen
bonding patterns do not explain the stability trend. We find that ill-deined concepts
like hydrophobicity and its myriad of related scales obfuscate, and are no longer
required, as we can rigorously use and define the repulsive and attractive aspects of
the van der Waals interaction in solution.
ACKNOWLEDGMENTS
The author thanks D. W. Bolen for many years of stimulating conversations. Partial
support is acknowledged from the National Institutes of Health GM037657, and the
R. A. Welch Foundation.
