Conditional solvation of isoleucine in model extended and helical peptides: context dependence of hydrophobic hydration and the failure of the group-transfer model

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, usually including factors to account for the solvent-exposure of the side-chain in the protein, have anchored the interpretation of seminal experimental studies in understanding protein stability and folding. Using simulations we show that such procedures to model protein hydration thermodynamics have significant limitations. We study the conditional hydration thermodynamics of the isoleucine side-chain in an extended pentapeptide and in helical deca-peptides using corresponding extended penta-glycine or 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 approach to parse the hydration thermodynamics into chemical, packing, and long-range interaction contributions. The chemical contribution of g-butane, reflecting the contribution of solvent clustering within the defined inner-shell of the solute, 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 central interest in understanding hydrophobic hydration. The packing contribution for g-butane substantially overestimates the conditional packing of isoleucine. The net of such compensating contributions 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.