Coupling and Clustering in Molecular Dynamics Simulation Studies of Lipid Membrane Biophysics

The plasma membrane defines a eukaryotic cell, separating the cell's interior from its surroundings. Structurally, the plasma membrane is a lipid bilayer, composed of numerous different lipids and proteins. A biophysical approach to understanding this system examines the behavior of the liquid crystal phases of the membrane's lipids. In particular, membrane rafts, regions with distinct physical properties, may be studied in model membranes using coexisting liquid phases containing as few as three lipid components. The findings described in this dissertation employ Molecular Dynamics simulations, computational models of the physics of interacting atoms and molecules, to explore the biophysical chemistry of lipid bilayers. Coarse-grained Molecular Dynamics simulations use simplified molecular models, which makes reproducing spontaneous demixing into coexisting liquid phases computationally feasible. The first study presented uses coarse-grained simulations to examine coupling between the two leaflets of a model membrane. While most publications report alignment of like domains, this study shows that lengthening the acyl chains of the high-melting-temperature phospholipid component or increasing the cholesterol concentration yields an alignment of unlike domains, accompanied by the appearance of a significant presence of cholesterol at the bilayer midplane, between the leaflets. The second study takes a different approach to leaflet coupling, engaging in atomistic simulations of compositionally asymmetric bilayers. Different lipids are present in each leaflet of the plasma membrane, so an asymmetric composition offers a more physiological model. The work reveals that even a single-phase leaflet is coupled to a phase-separated leaflet, as it adopts slightly different physical properties in the regions interacting with different domains. This finding suggests that transmembrane communication through coupling can occur in cells. Finally, the third study considers the role of ions in clusters of phosphatidylinositol 4,5-bisphosphate (PIP2), a lipid that makes up a small fraction of the plasma membrane but plays an outsize role in cell signaling and the retrovirus lifecycle. It confirms experimental evidence that clusters form in the presence of divalent cations but not monovalent ones and examines the interaction of ions and lipids and the impact on the lipids' physical properties