Exploring complex cellular membranes containing lipids, cholesterols, proteins, and gangliosides using molecular simulations
Ekanayaka Mudiyanselage, Asanga Bandara
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Domains of different thermodynamic phases manifest in the cell membrane as a consequence of the complex interactions between lipids and proteins. One of the outstanding challenges in membrane biophysics is to understand the role played by the structural and dynamical heterogeneity of membranes in supporting cellular function. In particular, there remain fundamental open questions related to the role of proteins in lipid domain formation, the effect of protein co-localization with lipid domains, and the nanoscopic structure of lipid domains. My dissertation research systematically investigated cellular membrane environments using all-atom and coarse-grained molecular simulations. Systems of incremental complexity, binary and ternary lipid model membranes, laterally heterogeneous membranes with proteins, and membranes with gangliosides were studied. With the aid of statistical mechanics and molecular simulation algorithms, critical insights were gained into cholesterol aggregation in model membranes. Cholesterol was found to populate a dimer ensemble with distinct sub-states in contrast to the idealistic view of face-flush cholesterol dimers. Further investigations characterized the inter- and intra-leaflet interactions of cholesterols, providing insights into possible trimer and tetramer formation. To probe the dynamic interplay of lipids and proteins in lipid raft-mimicking environments, we accurately modeled laterally heterogeneous membranes and explored the colocalization of transmembrane proteins. The proteins were observed to preferably co-localize at the domain boundaries, reducing the excess free energy of forming an interface. This observation has implications in transmembrane proteins known to be involved in the biogenesis of amyloid beta protein and believed to have activity dependent on localization in raft domains. Venturing beyond ternary lipid mixtures, membranes formed from quaternary lipid mixtures that approximate the surface of an artificial virus nanoparticle were examined. The effects of cations in mediating the interactions of negatively charged lipids were established through collaborative of experimental and simulation studies. Finally, development of force field parameters for sulfated poly-amido-saccharides and also validating existing cholesterol parameters across all available force fields were also undertaken as major methodological pursuits. Taken together these studies demonstrate the power of computer simulation, well-validated by experiment, to elucidate the structural and functional nature of complex biomolecular systems.