COMPUTER SIMULATION OF AMPHIPHILIC AGGREGATES

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Computer simulation calculations are proposed to complement several NIH funded experimental programs currently underway at Penn that involve the study of membrane-proteins, their structure and function. Specifically, we aim to investigate the binding of small proteins to membrane mimetic substrates and to attempt studies of the membrane-bound portions of certain proteins in a 'realistic' environment. One system we have in mind consists of cytochrome c tethered to self-assembled monolayers (SAMs) composed of lipid molecules. The SAMs in question will be monolayers chemisorbed to a solid substrate with specific polar endgroups (e.g., NH2) that electrostatically bind the cytochrome c. Another theme will deal with the structure of membrane-bound portions of certain proteins (or small membrane proteins) and the nature of their interaction with the host membrane. Initial studies will focus on the realistic modeling of phospholipid monolayers and bilayers with concomitant investigation of the protein segments via vacuum MD studies. The final goal here is the computer simulation of a coupled membrane- protein system and comparison with NMR data. These projects are logical evolutions of our current NIH funded research program. Two new initiatives are also proposed herein. The first will attempt to characterize the interaction of commonly used anesthetic gases with alpha-helical proteins. Here, the goal is a detailed understanding of how and where inhalation anesthetics bind to proteins and other cellular constitutuents. The second involves modeling studies on both 'real' and synthetic channel proteins. The latter have been designed to help illucidate and hence control the mechanism of protein function. In summary, state-of-the-art computer simulation calculations are proposed as a means to probe certain fundamental aspects of membrane-protein interactions. To this end, new simulation codes and computational methodologies will undoubtedly need to be developed. The long-term goal is to complement the experimental programs of my colleagues at Penn: Profs. Dutton and Eckenhoff in the Medical School and Profs. Blasie and Opelia in the Dept. of Chemistry.