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Title: Kinetics and Thermodynamics of Interaction between Amphiphiles and Membranes: Interplay of Amphiphile Dipole Moment and Membrane Dipole Potential
Authors: Cardoso, Renato Manuel Soares 
Orientador: Silvestre, Maria João Pedrosa Ferreira Moreno
Vaz, Winchil Luís Cláudio
Keywords: Dipole Moment; Kinetics; Thermodynamics; Membrane Dipole Potential
Issue Date: 14-Jan-2014
Citation: CARDOSO, Renato Manuel Soares - Kinetics and thermodynamics of interaction between amphiphiles and membranes : interplay of amphiphile dipole moment and membrane dipole potential. Coimbra : [s.n.], 2013. Tese de doutoramento. Disponível na WWW:
Abstract: The passive permeation across biological membranes is a main route determining a drug bioavailability. However, the prediction of its permeability requires the quantitative knowledge of the kinetic parameters for interaction with the distinct membrane barriers (insertion, desorption and translocation). For most drugs this kinetic profile is unknown and their permeability rate is estimated based on their general hydrophobicity, accessed through partition between octanol and water. Considering that membranes are highly anisotropic systems, the comparison with homogenous phases is simpleminded. The orientation of the lipids in membranes, with their polar groups oriented to the aqueous phase and the non-polar hydrocarbon chains oriented towards the bilayer mid-plane, generates transversal gradients of polarity, density and charge. One important property that arises from this asymmetry is the dipole potential. Moreover, most drugs and biological ligands have an asymmetrical charge distribution, and the interplay between the amphiphile dipole moment and membrane potential is expected to play a important role in their interaction parameters. This question has however been overlooked by the scientific community. In this work we presented a detailed study of the kinetics and thermodynamics of the interaction between two fluorescent amphiphilic molecules, RG-C14 and CBF-C14, and membranes with distinct lipid compositions characteristic of eukaryotic cell membranes. Furthermore, their relative water/bilayer partition coefficient and solubility in distinct membranes, as well as the location at the membrane interface, were recovered. The probes were chosen to have an opposite dipole moment orientation, once inserted in the bilayer, and a hydrophobic chain of 14 carbons length. The experimental results were rationalized in terms of the membrane dipole potential, whose value was determined for the lipid compositions of interest using monolayers. The well-established condensation effect of cholesterol promotes lipid packing and, consequently, the dipole potential is increased. The carbonyl group in the sn-2 acyl chains of phospholipids showed a preponderant role in the final dipole potential, and its absence in SpM leads to a decrease in the dipole potential. The results obtained allow the prediction of the dipole potential profile of the asymmetric plasma membrane, enriched in SpM and cholesterol in the outer and with significant amounts of PE and PS in the inner monolayer. Interestingly, it is found that the dipole potential reinforces the observed transmembrane potential. The RG-C14 showed a smaller aqueous solubility than CBF-C14, revealing its more hydrophobic character. Moreover, RG-C14 showed a tendency to aggregate when inserted in the membranes, especially for bilayers in the liquid ordered phase (POPC:CHOL(5:5) and SpM:CHOL(6:4)). The relative partition coefficient, of both probes, between POPC and the different acceptor membranes, showed a linear decrease with the membrane dipole potential for POPC:CHOL membranes. Moreover, the slope was higher for the RG-C14 (same dipole orientation has the membrane) than for CBF-C14 indicating a higher stability for the latter in the liquid ordered phases. The characterization of the kinetics and thermodynamics for the interaction of both CBF-C14 and RG-C14 with the different lipid bilayers performed in this work represents a major step forward in the currently available literature on this subject. The results obtained lead to the establishment of rules for the interplay between the amphiphiles dipole moment and the membrane dipole potential. We observe that for desorption of RG-C14 is slower than that of CBF-C14, in agreement with a stabilization of the inserted state for RG-C14. For the transbilayer movement of the probes, it was observed that the rate of translocation was faster for RG-C14 than for CBF-C14, in agreement with the more polar headgroup for the CBF-C14 (negative charge). The interaction between the amphiphile dipole moment and the membrane dipole potential at the different location of the amphiphiles (inserted state at equilibrium and transition states for desorption/insertion and translocation) contributes significantly to the overall energy of the distinct states, and is particularly evident in the enthalpic term. The enthalpy variations upon formation of the transition state in both desorption and translocation was more unfavorable for RG-C14 than for CBF-C14, in agreement with a more stabilized state of RG-C14 when inserted in the membrane. This was attributed to the attractive force between the dipole moment of RG-C14, when inserted in the bilayer, and the dipole potential of the membrane while it is repulsive for the case of CBF-C14.
Description: Tese de doutoramento em Química, apresentada à Faculdade de Ciências e Tecnologia da Universidade de Coimbra
Rights: embargoedAccess
Appears in Collections:FCTUC Química - Teses de Doutoramento

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