Physical Considerations of the Organization of Inclusions in Lipid Bilayer Systems

Lipid bilayers, along with embedded inclusions such as cholesterol and proteins, constitute a biological membrane—the interface between a cell or organelle and its environment. Understanding the structure of a biological membrane and the physical principles responsible for the organization of membrane inclusions is crucial to understanding the processes that occur on the surface of a cell or organelle such as inter-cellular signaling, immune synapse processes, exo- and endocytosis, and membrane fusion. In this work, we study the organization and effect of inclusions in a lipid bilayer using statistical mechanics principles and large-scale molecular simulations.In the first part of this work, we propose a generic physical force for the assembly of inclusions in lipid bilayers—the orderphobic effect. Inspired by modern theories of the hydrophobic effect, this force is governed by the physics of the first-order phase transition between the ordered (i.e., solid-like) and disordered (i.e., fluid) phases of lipid bilayers. We show the existence and nature of this force using coarse-grained molecular dynamics simulations, and demonstrate the lateral assembly of two model proteins, or ‘orderphobes’, within a lipid bilayer. The effect is powerful and operates at nano- to mesoscopic scales, and could be a potential explanation for the clustering of proteins in a biological membrane.In the second part of this work, we focus on hydrophobic inclusions within the lipid bilayer that give rise to organelles known as lipid droplets. These droplets, earlier thought to be passive stores of hydrophobic material in an otherwise aqueous cytosol, have now been implicated in various metabolic diseases. Since the growth and behavior of nascent droplets is sub-microscopic, little is known about the details of this process. We construct a computational framework that allows for a lipid reservoir to study asymmetric inclusions in a lipid bilayer such as the lipid droplet. Further, we identify key stages in the growth and budding of this organelle