  The hydration thermodynamics of the GXG tripeptide relative to the reference
GGG is often used to define the conditional hydration contribution of X. This
quantity or the hydration thermodynamics of a small molecule analog of the
side-chain or some combination of such estimates, have anchored the
interpretation of seminal experiments on protein stability and folding. We show
that such procedures to model protein hydration have significant limitations.
We study the conditional hydration thermodynamics of the isoleucine side-chain
in an extended pentapeptide and in helical deca-peptides, using as appropriate
an extended penta-glycine or appropriate helical deca-peptides as reference.
Hydration of butane in the gauche conformation provides a small molecule
reference for the side-chain. We use the quasichemical theory to parse the
hydration thermodynamics into chemical, packing, and long-range interaction
contributions. The chemical contribution reflects the contribution of solvent
clustering within the defined inner-shell of the solute; the chemical
contribution of g-butane is substantially more negative than the conditional
chemical contribution of isoleucine. The packing contribution gives the work
required to create a cavity in the solvent, a quantity of interest in
understanding hydrophobic hydration. The packing contribution for g-butane
substantially overestimates the conditional packing of isoleucine. The net of
such compensating contributions still disagrees with the conditional free
energy of isoleucine but by a lesser magnitude. The excess enthalpy and entropy
of hydration of g-butane model are also more negative than the corresponding
conditional quantities for the side-chain. The conditional solvation of
isoleucine in GGIGG also proves unsatisfactory in describing the conditional
solvation of isoleucine in the helical peptides.
