Thermodynamics of Membrane Partitioning for a Series of n-Alcohols Determined by Titration Calorimetry:  Role of Hydrophobic Effects

Abstract

Recent studies have shown that the traditional paradigm relying on hydrophobic effects is not adequate to describe membrane partitioning of amphiphilic solutes. To elucidate the thermodynamics and determine the role of the hydrophobic effect in the partitioning of small amphiphilic molecules into lipid bilayers, we have used titration calorimetry to directly measure the enthalpy, partition coefficients, and heat capacity change for the partitioning of a series of n-alcohols into lipid bilayers of several lipid compositions. The incremental thermodynamic quantities have been compared with model compound data for partitioning into bulk hydrocarbon solvents. We have found that there is a large negative heat capacity change upon partitioning, indicating a major contribution from the dehydration of nonpolar solute moieties; however, these hydrophobic effects also involve changes in lipid interactions with water in the interfacial region of the bilayer. In addition, we have found that the enthalpy effects are large, indicating that the partitioning process is accompanied by significant changes in the intralipid interactions within the bilayer. Cholesterol has a large effect on partitioning thermodynamics, making both the enthalpy and entropy contributions significantly more positive, resulting in a relatively small net decrease in the negative free energy of partitioning. These results demonstrate that while hydrophobic interactions play a major role in partitioning, the process is considerably more complex than the partitioning of model compounds between water and bulk hydrocarbons, with major contributions coming from changes in the structure and thermodynamic state of the bilayer, including the interfacial region. The results are discussed in terms of both the thermodynamics of partitioning and the role of lipid properties in membrane function. Our results support a paradigm for membrane structure and function in which the thermodynamic state, which is a function of lipid composition, temperature, and dissolved solutes, is a critical membrane property.

Using spin polarised positive muons for studying guest molecule partitioning in soft matter structures

“…Inspection of Table 7 reveals that ΔH tr and TΔS tr are of similar magnitude in all considered cases, resulting in very small ΔG tr values, which is not so for aliphatic alcohols that are transferred from water to the bilayer [39], probably because of their lower polarizabilities cavity work of the solute.…”

“…The molecular interpretation of the classical version of the hydrophobic effect consists of two contributions: hydrophobic hydration and hydrophobic interaction [36][37][38] focuses on the effect on water structure in the presence of nonpolar moieties [39].…”

“…It is associated with a further decrease of the negative enthalpy of transfer upon the penetration of the solute into the membrane, indicating that it participates in the lipid-lipid interaction and enhances it, which is called the 'bilayer effect' [39,47]. A negative increment of the enthalpy and entropy of transfer per additional methylene group is characteristic of partitioning into the membrane [39,46,47].…”

“…It is well known that apolar solutes such as higher phenyl alcohols are only slightly miscible with water, which is attributed to their hydrophobicity. At a molecular level, the transfer of the muoniated alcohol from the aqueous environment into the surfactant bilayer, which is characteristic for the nonclassical hydrophobic effect [39,46] and can be described by the equilibrium, radical(water) radical(bilayer). Introduction of the solute into water, however, involves the disruption of its interactions with the DHTAC amphiphiles, a cavity creation in water, and the initiation of alcohol-water interactions which is typical for the classical hydrophobic effect [36].…”

“…The partitioning of the same species into the lipid bilayers is primarily driven by the nonclassical hydrophobic effect [39,47].…”