Energetics of Inclusion-Induced Bilayer Deformations

Abstract

The material properties of lipid bilayers can affect membrane protein function whenever conformational changes in the membrane-spanning proteins perturb the structure of the surrounding bilayer. This coupling between the protein and the bilayer arises from hydrophobic interactions between the protein and the bilayer. We analyze the free energy cost associated with a hydrophobic mismatch, i.e., a difference between the length of the protein's hydrophobic exterior surface and the average thickness of the bilayer's hydrophobic core, using a (liquid-crystal) elastic model of bilayer deformations. The free energy of the deformation is described as the sum of three contributions: compression-expansion, splay-distortion, and surface tension. When evaluating the interdependence among the energy components, one modulus renormalizes the other: e.g., a change in the compression-expansion modulus affects not only the compression-expansion energy but also the splay-distortion energy. The surface tension contribution always is negligible in thin solvent-free bilayers. When evaluating the energy per unit distance (away from the inclusion), the splay-distortion component dominates close to the bilayer/inclusion boundary, whereas the compression-expansion component is more prominent further away from the boundary. Despite this complexity, the bilayer deformation energy in many cases can be described by a linear spring formalism. The results show that, for a protein embedded in a membrane with an initial hydrophobic mismatch of only 1 A, an increase in hydrophobic mismatch to 1.3 A can increase the Boltzmann factor (the equilibrium distribution for protein conformation) 10-fold due to the elastic properties of the bilayer.

Elastic coupling of integral membrane protein stability to lipid bilayer forces

“…5B shows that m increases as the hydrophobic thickness and chain unsaturation of the bilayer increase. The former increases the local stress around the protein by lipid deformation (7,35), and the latter increases intrinsic curvature stress and lateral pressure in the bilayer (6). This interpretation is consistent with and supports the interpretation of the previously discussed changes of ⌬G u,H2O o .…”

“…Even if one uses smaller values of 15-20 cal͞mol͞Å 2 as commonly assumed in protein folding (33), it is clear that the hydrophobic effect grossly overestimates the experimental value. There must be opposing forces, such as mechanical energy stored in the membrane due to hydrophobic mismatch at the protein͞ lipid interface (35). Lipids need to be stretched if too short and compressed if too long compared to the hydrophobic 26 Å of the protein.…”

Atomistic insight into lipid translocation by a TMEM16 scramblase

“…This deformation thins the membrane by 36%, thus providing a shorter pathway for a hydrophilic headgroup to cross. The computed membrane distortion energy value for nhTMEM16 is 8-20 times higher than theoretical and experimental values for gramicidin (25,35) and rhodopsin (36) and about twice as high as values estimated for the membrane associated gating energy of the mechanosensitive channel of large conductance (MscL) (37,38). Because the leaflet-to-leaflet distance is still large (18.3Å), thinning is not likely the sole mechanism.…”

Cholesterol modulates the volume-regulated anion current in Ehrlich-Lettre ascites cells via effects on Rho and F-actin

“…Cholesterol depletion has been shown to disrupt the structure of rafts (4), including caveolae (67), and consequently, the effects of cholesterol on membrane protein function are frequently taken to indicate the involvement of rafts and/or caveolae. However, 1) cholesterol is known to bind directly to membrane proteins, thereby regulating their function (17), and 2) an increase in cholesterol content generally increases bilayer thickness (8), and stiffness (37), which modulate the "membrane deformation energy," a parameter dependent on bilayer thickness, mechanical properties, and monolayer equilibrium curvature, which has been used to describe the overall impact of these parameters on ion channel properties (25,38). The membrane deformation energy contributes to the overall energy cost of channel opening/closing, as shown for, e.g., gramicidin channels and voltage-dependent Na ϩ channels (31,32).…”