(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.
| Loll, Patrick J (2018) Structural Analysis of Anesthetics in Complex with Soluble Proteins. Methods Enzymol 603:3-20 |
| Yang, Elaine; Granata, Daniele; Eckenhoff, Roderic G et al. (2018) Propofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation-coupled inactivation. J Gen Physiol 150:1299-1316 |
| Woll, Kellie A; Guzik-Lendrum, Stephanie; Bensel, Brandon M et al. (2018) An allosteric propofol-binding site in kinesin disrupts kinesin-mediated processive movement on microtubules. J Biol Chem 293:11283-11295 |
| Woll, Kellie A; Zhou, Xiaojuan; Bhanu, Natarajan V et al. (2018) Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors. FASEB J 32:4172-4189 |
| Kasimova, Marina A; Yazici, Aysenur Torun; Yudin, Yevgen et al. (2018) A hypothetical molecular mechanism for TRPV1 activation that invokes rotation of an S6 asparagine. J Gen Physiol 150:1554-1566 |
| Wang, Yali; Yang, Elaine; Wells, Marta M et al. (2018) Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites. J Gen Physiol 150:1317-1331 |
| Bensel, Brandon M; Guzik-Lendrum, Stephanie; Masucci, Erin M et al. (2017) Common general anesthetic propofol impairs kinesin processivity. Proc Natl Acad Sci U S A 114:E4281-E4287 |
| Okuno, Toshiaki; Koutsogiannaki, Sophia; Ohba, Mai et al. (2017) Intravenous anesthetic propofol binds to 5-lipoxygenase and attenuates leukotriene B4 production. FASEB J 31:1584-1594 |
| Granata, Daniele; Ponzoni, Luca; Micheletti, Cristian et al. (2017) Patterns of coevolving amino acids unveil structural and dynamical domains. Proc Natl Acad Sci U S A 114:E10612-E10621 |
| Carnevale, Vincenzo; Klein, Michael L (2017) Small molecule modulation of voltage gated sodium channels. Curr Opin Struct Biol 43:156-162 |
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