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Pannexin-1 in silico modeling towards physiological and pathological functioning

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TitleInfo
Title
Pannexin-1 in silico modeling towards physiological and pathological functioning
Name (type = personal)
NamePart (type = family)
Subach
NamePart (type = given)
Joel
NamePart (type = date)
1967-
DisplayForm
Joel Subach
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Srinivasan
NamePart (type = given)
Shankar
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Shankar Srinivasan
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Frederick
NamePart (type = given)
Coffman
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Coffman Frederick
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Masayuki
NamePart (type = given)
Shibata
DisplayForm
Shibata Masayuki
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Dinesh
NamePart (type = given)
Mital
DisplayForm
Mital Dinesh
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Health Professions
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
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2020
DateOther (encoding = w3cdtf); (qualifier = exact); (type = degree)
2020-01
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Abstract (type = abstract)
The transmembrane pore protein Pannexin-1 (Panx1) forms channels allowing the release of purine nucleotides and participates in processes related to purinergic signaling, including blood pressure regulation, apoptotic cell clearance, and neuropathic pain. Panx1 has also been implicated in several pathological mechanisms, including facilitating HIV entry. While several naturally occurring inhibitors of Panx1 activity have been discovered, elucidating structure-function relationships within the Panx1 oligomer and the ability to design molecules to regulate Panx1 activities has been limited due to the absence of a Panx1 crystal structure. To address this limitation, an in silico model of Panx1 was constructed, based on homologous protein channel structures, established physicochemical characteristics and binding properties of the Panx1 channel.

Homologous template protein searches, transmembrane topologies and sequence alignments were subsequently used by MODELLER software to generate Panx1 A-Chain monomer subunits via a multi-template stitching approach. These A-chain subunit models and a GalaxyWeb Panx1 sequence generated A-chain subunit were subsequently used to construct four model homo-oligomers (pentamers, hexamers, heptamers, and octamers) using GalaxyWEB, all oligomeric structures were compared to established biophysical parameters of Panx1 channels. Docking experiments using Medusa Guide were performed using four small molecules and the 10Panx1 mimetic peptide known to block the Pannexin-1 channel. Docking simulation free energy results were used to assess the regional validity of the designed Panx1 model.

The optimum Pannexin-1 model was a hexameric structure exhibiting compact helices and dynamic loops and tails which promoted both pore and oligomer diameters and an overall structure matching Pannexin-1 experimental data. Docking experiments overall exhibited moderate affinity free energy values for Panx1 inhibitors inferring an overall fair modeling accuracy. A high affinity free energy value of -46.38 kcal mol-1 was discovered for the mimetic 10Panx1 which partially steric blocks the Pannexin-1 pore region.2, 8, 66 EL-1/2 docking results demonstrated high (< -30 to -50 kcal mol-1) to poor (> -20 kcal mol-1) affinities. The model suggested these small molecules bound to the EL1/2 regions primarily through steric/hydrophobic and polar interactions. Overall, this model fits with established experimental results and is a reasonable tool for the initial design of compounds which modulate Pannexin-1 gating.
Subject (authority = RUETD)
Topic
Biomedical Informatics
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_10501
PhysicalDescription
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InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xvi, 143 pages) : illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = LCSH)
Topic
Cell membranes
Subject (authority = LCSH)
Topic
Proteins
RelatedItem (type = host)
TitleInfo
Title
School of Health Professions ETD Collection
Identifier (type = local)
rucore10007400001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/t3-3mmg-3381
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Subach
GivenName
Joel
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2020-01-06 10:17:10
AssociatedEntity
Name
Joel Subach
Role
Copyright holder
Affiliation
Rutgers University. School of Health Professions
AssociatedObject
Type
License
Name
Author Agreement License
Detail
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.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical

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ETD
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windows xp
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2020-02-07T13:35:32
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2020-01-07T09:22:37
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