The Division of Materials Research and the Division of Molecular and Cellular Biosciences contribute funds to this award. This award supports theoretical research at the intersection of condensed matter physics, membrane biology, and structural biology. The PI will explore the physical principles underlying the spatial organization and biological function of cell membranes. Cell membranes exhibit a complex organization of lipids and membrane proteins, and play an integral role in many cellular processes. The functional properties of membrane proteins are not purely determined by protein structure but, rather, membrane proteins act in concert with the surrounding lipid bilayer. The overall objective of this project is to relate recent insights into the molecular structure of membrane components, which have resulted from a number of seminal breakthroughs in structural biology, to the coarse-grained description of cell membranes in terms of continuum elasticity theory, thereby providing a bridge between the structure of membrane proteins and the organization and biological function of cell membranes. Linking membrane mechanics to membrane protein structure requires a theoretical approach going beyond previous elastic models of membranes, which have mostly focused on cylindrical or conical membrane inclusions at large separations. Cell membranes are crowded, with the size and spacing of membrane proteins both being of the order of a few nanometers, and membrane proteins are found to exhibit a rich variety of hydrophobic shapes. The PI aims to develop a versatile elastic description of cell membranes allowing for the complex shapes of membrane proteins obtained from structural biology, and permitting the analysis of interactions among a large number of membrane inclusions in close proximity, which is the experimental scenario most relevant for the crowded membrane environment provided by living cells.
The general theoretical concepts developed through this project will be employed to address specific biological questions in three model systems. First, the functional characteristics associated with the various reported oligomeric states and structures of mechanosensitive ion channels will be predicted in the form of channel gating curves with varying membrane tension. Second, the minimum energy shapes of membrane protein polyhedra - faceted bilayer vesicles of well-defined polyhedral symmetry - will be related to the properties of the constituent lipids and membrane proteins. Third, the planned research will explore the impact of membrane-mediated elastic interactions on the spatial organization and cooperative signaling exhibited by chemoreceptor lattices. These three case studies will enable the systematic exploration of the relationship between the structure of membrane components and the spatial organization and functional properties of cell membranes.
This supports educational activities across a range of age groups, including two graduate students who will (1) help to mentor undergraduate research assistants, (2) participate in outreach activities to local high schools, (3) collaborate closely with researchers across different academic departments and institutions, (4) engage in minority outreach programs, and (5) participate in the development and teaching of a new course at the interface of physics and biology. This project supports high school science education in central Los Angeles through the organization of workshops for inner-city high school science teachers.
NONTECHNICAL SUMMARY The Division of Materials Research and the Division of Molecular and Cellular Biosciences contribute funds to this award. This project explores the physical principles underlying the biological function of proteins embedded in cell membranes, and supports research at the intersection of condensed matter physics, membrane biology, and structural biology. Membrane proteins are an abundant and important class of molecules that play critical roles in many human diseases, including cancer and Alzheimer's. Recent years have seen several major breakthroughs in the structural elucidation and biophysical characterization of membrane components. The biological function of membrane proteins is generally determined by a complex interplay between protein structure and the properties of the surrounding lipid bilayer, a major component of the membrane. This leads to a deformation of the membrane from its unperturbed state which can be described quantitatively using the theory of continuum elasticity, which has been studied widely in the context of materials research. This project develops the continuum elasticity theory of membranes as a bridge connecting the structure of membrane components to the organization and biological function of cell membranes in vivo.
The general theoretical concepts developed in this project will be employed to address specific biological questions in three model systems. The first of these model systems concerns mechanosensitive ion channels, which are membrane proteins that can respond to mechanical stimuli and constitute and form the basis for the sense of touch, for example. The second model system concerns membrane protein polyhedra, which have been proposed as a novel tool for the structural study of membrane proteins. Finally, the third model system concerns chemoreceptors which form the basis for the sense of smell, for example. Chemoreceptors provide a widely-studied example of membrane proteins able to transmit signals across cell membranes, and which have been shown recently to exhibit an intriguing spatial organization into regular lattice structures. These three case studies represent model systems of high experimental interest, and will allow the systematic exploration of the relationship between the structure of membrane components and the spatial organization and functional properties of cell membranes.
The scientific goals of this project are complemented by a range of educational activities which will (1) support graduate, undergraduate, and high-school students, (2) lead to the development of a new course at the interface of physics and biology, and (3) support high school science education in central Los Angeles through the organization of workshops for inner-city high school science teachers.
