This award supports theoretical research and education in biological physics. The research involves a series of increasingly sophisticated models of biological membranes which are designed to elucidate salient structure in the organization of molecules in the membrane. This idea, that molecules in the membrane of a cell are not distributed uniformly, underlies a set of new research questions. The underlying hypothesis is that the distribution of proteins and other molecules, such as cholesterol, in the cell membrane leads to functional organization, i.e. this organization can affect a host of other biologically important processes such as cell signaling, membrane fusion, viral entry and a variety of other functions which involve the cell membrane. Techniques of statistical mechanics and simulation will be used to explicate behaviors of model bilayer membranes consisting of cholesterol, saturated and unsaturated lipids with specific goal of observing the phase separation in this quasi-two dimensional fluid.
Three specific phenomenon are highlighted in this research. The first attempts to identify sound theoretical basis for the existence (or nonexistence) and properties and dynamics of membrane rafts. Such rafts, described as regions of saturated lipids and cholesterol that had aggregated and float together. The functionality which is associated with rafts derives from the attachment of signaling proteins to the edges of the raft and thereby providing structural organization for signaling processes the couple the interior and exterior of the cell.
NON-TECHNICAL SUMMARY: This award supports fundamental theoretical research and education on the biological physics of cell membranes. Scientific understanding of living cells has clearly shown that the cell membrane is complex and sophisticated in its functionality, doing far more than simply acting as a container holding the contents of the cell in place. With new understanding that the molecules that form the membrane are not entirely disorganized, there have developed a number of conjectures of how the intrinsic structure in a cell membrane may organize the way biological processes occur in the region where transport of signaling occur between the cell interior and its external environment. The research will employ tools of theoretical physics and use computer simulations to describe the organization of molecules in groups in the membrane. These tools allow researchers to establish what sort of structures can exist in the membrane and whether this pays an essential role in allowing the cell to carry out the essential life processes. A key concept of cell membrane organization is that the membrane includes floating groups of molecules which carry specialized signaling molecules or other proteins involved in allowing the cell to communicate with its environment.
This research will be conducted with the full participation of graduate students, who will be trained in modern methods of theory and computer simulation as applicable to biological systems, preparing them for careers in science and biotechnology. Finally the research will be performed in collaboration with scientists from the US and abroad, strengthening and enriching the US physical community.
There has been enormous interest in the hypothesis that the plasma membrane, which surrounds all cells, is not uniform and homogeneous but rather is inhomogeneous, consisting of regions of cholesterol and saturated lipids, like sphyingomyelin, floating like rafts ina a sea of unsaturated lipids. This project investigated theoretically several aspects of such rafts. The major interest is that proteins could tell the difference between rafts and sea and therefore would aggregate in one or the other and be more efficient. I think our most important result was a calculation of how much certain proteins do prefer the raft or the sea. We found that whereas there was not a large difference between proteins inserting into a raft, the sea definitely preferred one kind of protein to another. We also showed that rafts in the two leaves of the plasma membrane would be very well correlated, which would contribute to more efficient functioning. Another result was to show how crosslinking, which is often the first step in a biological process, would lead to the formation of rafts. We also showed that membrane tension, brought about for example by linkage to the underlying cytoskeleton, would decrease the temperature of the phase separation commonly seen in model systems. This inspired an experiment here at the UW to verify that this was correct and did so. Finally on this subject, a model was proposed that views the raft as a dynamic entity, a microemulsion, that is induced by thermal fluctuations in the membrane. It appears to be a very encouraging hypothesis. These projects developed resources in Science and Engineering by providing a solid background to my student. He was offered, and accepted, a Post-doctoral Fellowship. In addition, training in biological science research was provoded to an undergraduate Physics major. He is now employed at an imaging lab at UC Irvine. Finally this work, and others on the fusion of membranes has been presented at annual meetings of the Biophysical Society and at various seminars.
