Cooperative Gating and Spatial Organization of Membrane Proteins through Elastic Interactions

Abstract

Biological membranes are elastic media in which the presence of a transmembrane protein leads to local bilayer deformation. The energetics of deformation allow two membrane proteins in close proximity to influence each other's equilibrium conformation via their local deformations, and spatially organize the proteins based on their geometry. We use the mechanosensitive channel of large conductance (MscL) as a case study to examine the implications of bilayer-mediated elastic interactions on protein conformational statistics and clustering. The deformations around MscL cost energy on the order of 10 k_BT and extend ∼3 nm from the protein edge, as such elastic forces induce cooperative gating, and we propose experiments to measure these effects. Additionally, since elastic interactions are coupled to protein conformation, we find that conformational changes can severely alter the average separation between two proteins. This has important implications for how conformational changes organize membrane proteins into functional groups within membranes. Membranes form flexible boundaries between the interior of a cell and its surrounding environment. Proteins that reside in the membrane are responsible for transporting materials and transmitting signals across these membranes to regulate processes crucial for cellular survival. These proteins respond to stimuli by altering their shape to perform specific tasks, such as channel proteins, which allow the flow of ions in only one conformation. However, the membrane is not just a substrate for these proteins, rather it is an elastic medium that bends and changes thickness to accommodate the proteins embedded in it. Thus, the membrane plays a role in the function of many proteins by affecting which conformation is energetically favorable. Using a physical model that combines membrane elastic properties with the structure of a typical membrane protein, we show that the membrane can communicate structural and hence conformational information between membrane proteins in close proximity. Hence, proteins can “talk” and “respond” to each other using the membrane as a generic “voice.” We show that these membrane-mediated elastic forces can ultimately drive proteins of the same shape to cluster together, leading to spatial organization of proteins within the membrane.