Osmophobics and Hydrophobics - Fluctuation Theory of Solutions - page 322

Short oligomers have relatively simple conformational possibilities. Those calcula-
tions therefore did not require extensive conformational sampling.
One can then ask what would longer oligomers of Gly n that have nontrivial confor-
mational possibilities do. We initially chose Gly 15 , which had been used as a model
for denatured states in water and urea solutions (Tran, Mao, and Pappu 2008). We
asked whether TMAO can compact Gly 15 . We found that Gly 15 is compact in water
but the radius of gyration and its probability distribution shrinks in TMAO (Hu et al.
2010b). Given this and the expansion in urea solution (Tran, Mao, and Pappu 2008)
we have our first hypothesis from comparing the mechanism of folding of Gly 15 to
the mechanism of solubility of Gly 5 . We hypothesize the solvation free energy driv-
ing force causing the compaction of Gly 15 in water and TMAO is mechanistically
related to the low solubility limit of Gly 5 through ΔG precip or ΔG sep .
We (Hu et al. 2010b) and others (Tran, Mao, and Pappu 2008) have found that
hydrogen bonding within the peptide solute, in this case oligo glycine, is not suf-
ficient to explain the collapse and the correct response to urea denaturation and
TMAO compaction. Dipolar solute-induced phase separation (Kirkwood 1934) has
been implicated before for peptide conformationally-dependent free energy land-
scapes (Perkyns, Wang, and Pettitt 1996).
12.4 CONCLUSIONS
Classically, the effects of varying solvent composition are decomposed into elec-
trostatic and hydrophobic effects. Recent reexamination of the classic Tanford
experiments on contributions to change in solvation free energy differences (Auton,
Holthauzen, and Bolen 2007), along with consideration of what constitutes hydro-
phobicity (Chandler 2005) brings into question this taxonomy. Given the work
reviewed above, we prefer to use a more natural set of variables, electrostatic and van
der Waals interactions, which are conveniently part of the underlying intermolecular
interaction models, to show the mechanistic trends of solution (de)stabilization.
The experimental measurements have been analyzed both with (Auton,
Holthauzen, and Bolen 2007) and without (Auton and Bolen 2005) activity cor-
rections to obtain changes in free energy and apparent free energy changes. What
remains is our interpretation in terms of what the molecules are doing and why. By
using models, whose fluctuations are more straightforward to explore and decom-
pose than nature, we can test various results of experiment and theories.
Others have postulated that the free energy penalties associated with cavity for-
mation or the vdW component increases in a nontrivial manner with chain length
(Tran, Mao, and Pappu 2008). This is interesting when compared to our detailed free
energy calculation results, which were specifically decomposed into the vdW and
electrostatic components. A central problem which has been revealed recently is that
our understanding of cavity hydration in terms of the hydrophobic effect (Pratt and
Chandler 1977; Chandler 2005) has changed in light of the nontrivial considerations
of the relatively weak van der Waals attractive forces' effects on water structure
and whether a completely dry cavity is a reasonable model of biopolymer-water
interfacial hydrophobicity (Choudhury and Pettitt 2005b, 2007). Taking the non-
electrostatic attractive forces into account produces a qualitatively different picture