INTERACTION OF INHALATIONAL ANESTHETICS WITH MACROMOLECU

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Led by Dr. Roderick G. Eckenhoff, the investigators propose to examine the binding interactions of inhalational anesthetics in general and halothane in particular with simple protein and lipid molecules chosen as well defined models. The main objective is to determine the structural and dynamic consequences of anesthetic binding to these model systems in order to understand the nature of anesthetic binding sites and the general consequences of anesthetic binding with respect to protein conformation. The program project consists of three experimental components, one component dedicated to molecular modeling, a core facility for the synthesis of peptides required by the program, and a modest administrative core. Project I (Dr. Roderick G. Eckenhoff) will characterize the extent and location of anesthetic binding to simple peptide, lipid, and lipid-peptide systems. Photoaffinity labeling methods will be used to study low affinity structure, and pure as well as protein containing lipid bilayers. Project II (Dr. Jonas Johannson) will examine anesthetic partition into various organic solvents and use this information to design and assay more complex, four-alpha-helix bundles with respect to the conformational and dynamic consequences of anesthetic binding. Project III (Dr. Paul A. Liebman) will focus on larger protein molecules, including heterotrimeric GTP binding proteins with respect to anesthetic binding and its effects on folding stability and function. Project IV (Dr. Michael A. Klein) will use computer simulations to achieve a quantitative understanding of these systems at the molecular level. Molecular dynamic simulations will be applied to the partition of halothane and isoflurane into model solvents, the interaction of these anesthetics with model peptides, lipid membranes, and ion channels in lipid membranes.