Nicotinic acetylcholine receptors (nAChRs) are pentameric Ligand Gated Ion Channels that are critical to signaling across synapses and the neuromuscular junction; such signaling is facilitated by high densities of nAChRs in the post-synaptic membrane. Organization of nAChRs, including partitioning behavior in membranes containing dis- tinct lipid domains, is poorly characterized. Numerous experimental studies have shown nAChR gain-of-function likely caused by direct interactions with cholesterol, but a significant role for lipid domains has been suggested by nAChR gain-of-function upon bulk cholesterol depletion. Furthermore, the opportunity for cholesterol to have a direct interactions will likely have a complex dependence on the extent of domain formation and lipid species in the membrane, which has not been previously addressed. In the present research, we use Molecular Dynamics Simulations with coarse-grained resolution via the MARTINI model to investigate concentrations of cholesterol and other lipids local to nAChRs embedded in complex model membranes with a range of head groups and degrees of unsaturation. Cholesterol and unsaturated lipids are observed binding in deep non-annular sites in the nAChR bundle (based on the 2BG9 cryo-EM structure), consistent with our previous predictions. nAChR partitions, however, into cholesterol-poor phases, resulting in dynamic exchange between cholesterol and unsaturated phospholipids.
Subject (authority = RUETD)
Topic
Computational and Integrative Biology
Subject (authority = ETD-LCSH)
Topic
Lipids
Subject (authority = ETD-LCSH)
Topic
Nicotinic receptors
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_7392
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (iv, 27 p. : ill.)
Note (type = degree)
M.S.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Liam M. Sharp
RelatedItem (type = host)
TitleInfo
Title
Camden Graduate School Electronic Theses and Dissertations
Identifier (type = local)
rucore10005600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.