9631050 Jakobsson The general objectives of the proposed work are to improve our understanding of the physical principles underlying the structure and functional mechanisms of biological membranes. The methodologies employed are computer simulations and statistical mechanical theory. The overall strategy of our laboratory is to validate computational methods on relatively simple systems that are well characterized by experimental measurement. Then we can extend the methods to using them to explore more complex systems of biological interest. In ion channels, the simplest and best characterized channel is the antibiotic channel-former gramicidin. In membranes themselves, the simplest system is a homogenous lipid bilayer. Our initial approach then has been to use gramicidin channels and pure homogenous lipid bilayers as test systems to develop efficient and accurate methodologies for the simulation of membrane proteins and membranes themselves. We have now begun to use these methodologies to understand more complex systems of interest. These more complex systems include the gramicidin channel-lipid complex, biologically important specific ion channels, such as voltage-gated sodium and potassium channels, and membranes interacting with signal peptides and organic molecules. An ultimate goal is to understand the complete interactions of large proteins with membranes and to understand the structure of heterogenous membranes, that include proteins, different species of lipids, and other molecules such as cholesterol. But the necessary intermediate goal, which we are pursuing in the next phase of our laboratory's work, is to understand the details of the interactions of different types of molecules in the membrane environment. These details will provide the building blocks for the more comprehensive understanding that it our ultimate goal. %%% Membranes are the surfaces of the cells that make up the building blocks of all living things. The forces that cause biological membranes to fo rm are much like the forces that cause the formation of soap bubbles, but membranes are much more chemically complicated than soap bubbles. In fact, many physicists believe that biological membranes are the most complicated condensed matter (liquid or solid) in the known universe. The basic building blocks of biological membranes are fatty molecules called phospholipids. In addition to phospholipids, biological membranes have many proteins embedded in them that carry out important biological functions. These functions include transporting materials between the inside of the cell and the outside, and sending and receiving chemical signals from other cells. For many complicated systems, computer simulations can help in understanding how the systems work. This is because the computer can show details that are very hard to measure directly. The current project is to use computer simulations to see the details of how membranes form, and how they function. In the computer simulations, we can see details of the interactions between the membrane phospholipid molecules and the surrounding water, details of the interactions between phospholipid molecules and proteins in the membrane, and details of the protein function. This project looks especially at one type of membrane protein called an ion channel. Ion channels are proteins whose function is to move across the membrane charged atoms called ions. One of the ion channels studied in this project is gramicidin, an antibiotic which kills cells of other organisms when it is inserted in their membranes, by making them too leaky to ions. Other ion channels studied in this project are important in generating electrical signals in cells. The goal of the project is to contribute to a basic understanding of biological membrane function. This is important both because of the inherent fascination of this extremely complicated type of matter and also because of the importance of understanding how biological function comes from the behavior of individua l molecules. ***
