Fluctuations and membrane heterogeneity.

Biological membranes contain many specialized domains, ranging from tens of nanometers to several microns in size and characterized by different concentrations and compositions of protein. Because these domains influence membrane function, considerable attention has focused on understanding their origin. Here it is shown that number fluctuations and nonspecific interprotein interactions can lead to considerable heterogeneity in the distribution of membrane proteins, and to an associated submicron-scale domain structure. Number fluctuations were analyzed by modeling the membrane as a two-dimensional fluid containing interacting protein solutes. The characteristic size and lifetime of a domain in which one would expect to observe a fluctuation of specified magnitude was calculated; snapshots showing fluctuation-induced heterogeneity were generated by Monte Carlo simulation. Domain size was found to depend on the nature of the interprotein force (e.g., attractive or repulsive) and on the average protein concentration. Domain size was largest at low protein concentrations and in the presence of attractive interprotein forces, and was smallest at high protein concentrations and in the presence of repulsive interprotein forces. Domain lifetime was found to depend on domain size and on the diffusion coefficient of the proteins. In a 'typical' membrane containing 5-nm proteins with diffusion coefficient 10(-10) cm(2)/s at a density of 1000 proteins/microm(2), a 30% fluctuation will yield domains characterized by a 2-fold difference in local concentration; these domains persist over a distance of about 100 nm and have a lifetime of about 0.25 s. These results can be used to analyze the domain structure commonly observed in electron micrographs, and have implications for both number fluctuation and Monte Carlo studies of the distribution and dynamics of membrane proteins.