Lipid-Protein Electrostatic Interactions in the Regulation of Membrane-Protein Activities

NATALIA WILKE; BELEN DECCA; GUILLERMO G. MONTICH

Conductive Polymers Electrical Interactions in Cell Biology and Medicine

crc

Año: 2017; p. 200 - 215

Electrostatic interactions are inherently related to cell membrane processes. Strong electric fields are generated by gradients of ions between compartments separated by cell membranes, fixed net charges in the membranes and oriented dipoles. If we consider a protein molecule as a collection of dipoles, partial and net charges, it is easy to imagine that within the membrane milieu, the interactions with electric fields constitute an excellent tool to modulate their activity, conformation and functionality (Tsong, 1990; Astumian, 1994; Teissie, 2007; Marsh, 2008). As examples of the relevance of electrostatics in lipid membranes, we can consider that two fundamental processes that support the life on Earth, photosynthesis and respiration, rely in the generation of electrochemical gradients between aqueous compartments separated by a biological membrane. The development of a nervous system in complex organisms was also completely dependent on mechanisms that include electrochemical gradients and electrostatic control of protein activities to translate information. The components of lipid membranes in a living cell have a well-defined orientation and long range organization. In water, lipids assemble spontaneously in a large variety of structures, among them the bilayer (Gennis, 1989; Jakli and Saupe, 2006). Within the same lipid molecule, a water soluble-portion (the polar head group) coexists with a chemical group, the hydrocarbon tail, with low solubility in water. Lipids in the bilayer are held together not by covalent bonds but because the water insoluble-portion is segregated from the aqueous solvent (Tanford, 1980). The order and orientation are imposed by the thermodynamic preference of the head groups for being in contact with water and the hydrocarbon chains to segregate from the aqueous solvent. Van der Waals, hydration, hydrogen bonding and screened electrostatic interactions also participate in defining the membrane structure (Israelachvili, 2011).Proteins also acquire their structure as a consequence, to large extent, of a balance between opposing solubilities (Richards, 1999; Privalov, 1999). Side chains with remarkable different solubility in water are present in a given sequence of amino acids. In the aqueous medium the best solution to this thermodynamic pressure is to fold, hiding non polar residues in the inner core and exposing the polar, water-soluble residues to the solvent. The fate for some sequences is to be soluble or membrane-associated peripheral extrinsic proteins. For other sequences, the best solution is to fold and insert into the lipid membrane, optimizing the interactions of non-polar residues with the hydrophobic core of the membrane, yielding the trans-membrane intrinsic proteins. A static snapshot of a cell membrane is shown in Figure1. To highlight the dynamical nature of the ensemble, the bi-dimensional and rotational diffusion coefficients of the membrane components are indicated in this Figure 1.Chemical reactions are intrinsically vectorial: for a collision to be effective, reactants must be in a defined orientation relative to each other and the products leave the transition state in a defined direction. The anisotropic organization of the components in a biological membrane introduces geometrical and energetic restrictions that bring out in evidence the intrinsic anisotropy of chemical reactions.We find basically two different approaches in the literature, or a mixture of them, to evaluate the contribution and role of electrostatics in lipid-protein interactions. In some cases, the lipid membrane, protein molecule and electrolyte solution are considered as a continuous medium. In others, the discrete nature of charges and the microscopic arrangement of atoms and molecules are taken into account. The electric field E generated by a charge q at a distance r in a medium considered as a continuous is E=q/εo ε r, where εo is the permittivity of vacuum and ε is the dielectric constant. The dielectric constant depends on the nature of the medium, particularly its dielectric polarizability. The dielectric constant is a parameter that takes into account the shielding of the electric field produced by a continuous medium. But at a molecular level, the dielectric constant loses its meaning. Let us suppose we want to evaluate the energy difference between two configurations, in one of them two charges are separated by a distance r1 and in the other by r2. In a continuous medium, the energy difference is ΔE = (qq´/ εo ε) / (1/r2-1/r1). The dielectric constant is used to take into account the decrease of the electrostatic energy due to the material medium as compared to the vacuum. The situation is quite different if the discrete nature of the material, the charges and their fixed locations, are explicitly considered. In this case, it is the particular arrangement of chemical groups between charges that defines the change in energy between both configurations (Figure 2). The dynamic characteristics of the system also define how suitably it can be described by a continuous model: if the timescale for the charge separation is slow as compared to the fluctuation of charges in the medium, the electrostatic screening can be averaged to a dielectric constant. A rigorous and extensive analysis of this problem is addressed by (Warshell and Aqvist, 1991).