This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ultimate goal of our study is to understand the molecular mechanisms of general anesthesia. The immediate objective of our computational efforts is to elicit the molecular details of protein motions that are difficult to observe directly with experimental methods but are potentially crucial to the understanding of anesthetic actions on the channel proteins. We will focus on nAChRs that have been suggested to be potential targets for general anesthetics.
The specific aims for the study include (a) to perform large-scale MD simulations (10 ns or longer as needed, 3 repeats with different seeds) on open-channel structures of the (?1)2?1?? and the neuronal (?4)2(?2)3 and (?7)5 nAChRs in a fully hydrated membrane patch of 3:1:1 POPC:POPA:Cholesterol in the absence of anesthetics (control systems);(b) to identify anesthetic (halothane and isoflurane) interaction sites in the Torpedo (?1)2?1?? and the neuronal (?4)2(?2)3 and (?7)5 nAChRs in the open-channel state by performing flexible ligand docking and comparing with our own NMR data and with other published experimental results (e.g., mutagenesis and photoaffinity labeling);and (c) To repeat MD simulations parallel to (a) in the presence of the docked anesthetics. Hypotheses for the study: (1) anesthetics, being amphipathic, interact specifically with the interface between two adjacent TM2 subunits near the hydrophobic girdle in the aqueous pore and at the actuation points at EC-TM interface;(2) anesthetics mediate the hydrophobicity mismatch at one of the actuation points;(3) anesthetic effects are encoded as global changes at tertiary and quaternary structural level after extended MD equilibration;(4) anesthetic interaction with the actuation points at EC-TM interface alters the RMS fluctuation of the TM2 domains, and the interaction at the hydrophobic girdle within the pore profoundly affects the re-orientation of the hydrophobic side chains and the flickering of water passage.
|Yonkunas, Michael; Buddhadev, Maiti; Flores Canales, Jose C et al. (2017) Configurational Preference of the Glutamate Receptor Ligand Binding Domain Dimers. Biophys J 112:2291-2300|
|Earley, Lauriel F; Powers, John M; Adachi, Kei et al. (2017) Adeno-associated Virus (AAV) Assembly-Activating Protein Is Not an Essential Requirement for Capsid Assembly of AAV Serotypes 4, 5, and 11. J Virol 91:|
|Subramanian, Sandeep; Chaparala, Srilakshmi; Avali, Viji et al. (2016) A pilot study on the prevalence of DNA palindromes in breast cancer genomes. BMC Med Genomics 9:73|
|Ramakrishnan, N; Tourdot, Richard W; Radhakrishnan, Ravi (2016) Thermodynamic free energy methods to investigate shape transitions in bilayer membranes. Int J Adv Eng Sci Appl Math 8:88-100|
|Zhang, Yimeng; Li, Xiong; Samonds, Jason M et al. (2016) Relating functional connectivity in V1 neural circuits and 3D natural scenes using Boltzmann machines. Vision Res 120:121-31|
|Lee, Wei-Chung Allen; Bonin, Vincent; Reed, Michael et al. (2016) Anatomy and function of an excitatory network in the visual cortex. Nature 532:370-4|
|Murty, Vishnu P; Calabro, Finnegan; Luna, Beatriz (2016) The role of experience in adolescent cognitive development: Integration of executive, memory, and mesolimbic systems. Neurosci Biobehav Rev 70:46-58|
|Lee, Tai Sing (2015) The visual system's internal model of the world. Proc IEEE Inst Electr Electron Eng 103:1359-1378|
|Kuhlman, Chris J; Anil Kumar, V S; Marathe, Madhav V et al. (2015) Inhibiting diffusion of complex contagions in social networks: theoretical and experimental results. Data Min Knowl Discov 29:423-465|
|Jurkowitz, Marianne S; Patel, Aalapi; Wu, Lai-Chu et al. (2015) The YhhN protein of Legionella pneumophila is a Lysoplasmalogenase. Biochim Biophys Acta 1848:742-51|
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