Abstract
Membrane elastic properties, which are subject to alteration by compounds such as cholesterol, lipid metabolites and other amphiphiles, as well as pharmaceuticals, can have important effects on membrane proteins. A useful tool for measuring some of these effects is the gramicidin A channels, which are formed by transmembrane dimerization of non-conducting subunits that reside in each bilayer leaflet. The length of the conducting channels is less than the bilayer thickness, meaning that channel formation is associated with a local bilayer deformation. Electrophysiological studies have shown that the dimer becomes increasingly destabilized as the hydrophobic mismatch between the channel and the host bilayer increases. That is, the bilayer imposes a disjoining force on the channel, which grows larger with increasing hydrophobic mismatch. The energetic analysis of the channel-bilayer coupling is usually pursued assuming that each subunit, as well as the subunit-subunit interface, is rigid. Here we relax the latter assumption and explore how the bilayer junction responds to changes in this disjoining force using a simple one-dimensional energetic model, which reproduces key features of the bilayer regulation of gramicidin channel lifetimes.
Highlights
Membrane protein function can be regulated by changes in membrane lipid composition [1,2,3,4,5,6,7,8]
The latter, physical regulation is important because membrane protein properties change when the membrane lipid composition is altered [9], and because many bioactive molecules are amphiphiles that for thermodynamic reasons [10,11] will alter lipid bilayer properties, which may provide insight into why amphiphiles modify the function of numerous different membrane proteins [12,13,14,15], The diversity of membrane proteins that are regulated by a given amphiphile suggests that these compounds may alter membrane protein function by mechanisms that do not involve direct binding to the target protein
It is likely that changes in continuum membrane properties may, quite generally, regulate the function of bilayer-embedded proteins ranging from receptors over channels to transporters and pumps [9]. This is important because drugs – such as genistein [12], capsaicin [13], curcumin [15] and 2,3-butanedione monoxime [17], that may act through specific binding to their target protein over a given concentration range, alter the function of many different membrane proteins at higher concentrations: concentrations at which they modify, to varying degrees, the bulk continuum bilayer properties
Summary
Membrane protein function can be regulated by changes in membrane lipid composition [1,2,3,4,5,6,7,8]. It is likely that changes in continuum membrane properties may, quite generally, regulate the function of bilayer-embedded proteins ranging from receptors over channels to transporters and pumps [9] This is important because drugs – such as genistein [12], capsaicin [13], curcumin [15] and 2,3-butanedione monoxime [17], that may act through specific binding to their target protein over a given concentration range, alter the function of many different membrane proteins at higher concentrations: concentrations at which they modify, to varying degrees, the bulk continuum bilayer properties. These changes in bilayer properties can in turn affect the function of disparate membrane proteins [16], which may lead to undesired side effects [18,19]
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