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Liposomes as carriers of poorly water-soluble substrates: linear modelling of membrane systems with catalytic or binding sites of different facedness. Significance of experimental membrane partition coefficients and of kinetic and equilibrium parameters.

ABSTRACT: 1. A multiphasic modelling approach to systems containing membrane-bound receptors or catalytic sites and a liposomal preparation as a substrate carrier is described. Kinetic expressions are derived for a single-substrate enzymic reaction operating at constant liposome concentration or at a fixed substrate/liposome concentration ratio. 2. The assumption that accumulation of exchangeable components into the phospholipid bilayers can be described by linear bulk-phase partition leads to simple relationships between the initial reaction rate and (a) two kinetic coefficients (V and K'm), (b) the partition coefficients of the solutes for the lipid compartments of the membrane (Pms) and liposomal preparations (P1s) and (c) the total concentrations of substrate, membrane lipid and liposomal lipid. K'm is called the effective Michaelis constant. 3. For correct estimation of the coefficients V, K', Pms and P1s extrapolation to zero lipid concentration is required. 4. The distinction is introduced between hydrophilic and hydrophobic aqueous-faced sites, lipid-faced sites and mixed sites, i.e. sites overlapping an aqueous and a lipid region. For hydrophilic aqueous-faced sites K'm is equal to the true Km and for the other types of site to Km/Ps. For lipid-faced and for mixed sites Ps corresponds to the membrane partition coefficient Pms. For binding of homologous compounds to a hydrophobic aqueous-faced binding pocket Ps is the incremental site partition coefficient Pbss, which takes into account the energetic contribution to the binding process due to the hydrophobic tail of the ligands. 5. K'm accounts for any effects due to the facedness and nature of the enzymic sites. The dependence of the systems on the size of the lipidic partition compartment(s) is expressed exclusively by a distribution function F.6. When enzyme assays are performed with a series of chemically different substrates containing the same catalytically sensitive group, independence of K'm from partition indicates a hydrophilic aqueous-faced binding site. For the low-molecular-mass members of the homologous series a linear increase in -log (K'm) with the logarithm of the partition coefficient will be observed with any of the other site types considered 7. Equilibrium relationships for binding of a ligand to a membrane-bound receptor are also derived. 8. The significance of experimental membrane partition coefficients is discussed.

SUBMITTER: Heirwegh KP

PROVIDER: S-EPMC1135045 | biostudies-other | 1988 Aug

REPOSITORIES: biostudies-other

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Project description:The partitioning of compounds between aqueous and other phases is important for predicting toxicity. Although thousands of octanol-water partition coefficients have been measured, these represent only a small fraction of the anthropogenic compounds present in the environment. The octanol phase is often taken to be a mimic of the inner parts of phospholipid membranes. However, the core of such membranes is typically more hydrophobic than octanol, and other partition coefficients with other compounds may give complementary information. Although a number of (cheap) empirical methods exist to compute octanol-water (log k OW) and hexadecane-water (log k HW) partition coefficients, it would be interesting to know whether physics-based models can predict these crucial values more accurately. Here, we have computed log k OW and log k HW for 133 compounds from seven different pollutant categories as well as a control group using the solvation model based on electronic density (SMD) protocol based on Hartree-Fock (HF) or density functional theory (DFT) and the COSMO-RS method. For comparison, XlogP3 (log k OW) values were retrieved from the PubChem database, and KowWin log k OW values were determined as well. For 24 of these compounds, log k OW was computed using potential of mean force (PMF) calculations based on classical molecular dynamics simulations. A comparison of the accuracy of the methods shows that COSMO-RS, KowWin, and XlogP3 all have a root-mean-square deviation (rmsd) from the experimental data of ≈0.4 log units, whereas the SMD protocol has an rmsd of 1.0 log units using HF and 0.9 using DFT. PMF calculations yield the poorest accuracy (rmsd = 1.1 log units). Thirty-six out of 133 calculations are for compounds without known log k OW, and for these, we provide what we consider a robust prediction, in the sense that there are few outliers, by averaging over the methods. The results supplied may be instrumental when developing new methods in computational ecotoxicity. The log k HW values are found to be strongly correlated to log k OW for most compounds.

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Liposomes as carriers of poorly water-soluble substrates: linear modelling of membrane systems with catalytic or binding sites of different facedness. Significance of experimental membrane partition coefficients and of kinetic and equilibrium parameters.

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