MOLEC DYNAMIC SIMULATIONS OF INHALED ANESTHETIC INTERACTIONS W/PEPTIDES &LIPID

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION: (taken from the application). Computer simulation molecular dynamics (MD) techniques are proposed to complement experiments designed to elucidate the molecular mechanism of action of inhaled anesthetics (IAs). The goal is classification of molecular aspects of anesthetic pharmacokinetics. To this end, constant pressure and temperature MD simulations will be used to detail the interactions of IAs with model protein and lipid systems and thereby provide important complementary information to contemporary experiments. Specifically, this project will characterize the interactions of halothane and ether based IAs with structural motifs that are directly related to probable sites of action and binding. Detailed simulations will be performed on a-helical peptide bundles with demonstrated specific binding to halothane. The aim will be to examine the properties of the proposed binding cavity, its suitability to accommodate halothane molecules, other IAs, and binding selectivity using specific mutations. Potential energy functions will be developed for commonly used ether-based IAs, such as isoflurane and sevoflurane. These will be used in classical simulations of IAs interacting with peptide bundles. Ab initio calculations will be employed to probe the interactions between halothane/isoflurane and specific amino acids. Extensive simulations will be performed to elucidate the distribution and behavior of IAs in model membranes. The focus will be on possible differences between the distribution of halothane, ether-based IAs and non-anesthetics in model membranes of saturated and unsaturated lipids. These calculations will produce models to assist the design and analysis of neutron diffraction experiments. Simulation studies will be initiated on a membrane-bound synthetic (GCN4-based) peptide bundle, which binds IAs. The goal is to probe the interactions of IAs with a model trams-membrane a-helical bundle, which exhibits specific binding for IAs when inserted in a bilayer.