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Conformational characterization of the intrinsically disordered protein α-Synuclein
Descriptive
TitleInfo
Title
Conformational characterization of the intrinsically disordered protein α-Synuclein
SubTitle
a replica exchange molecular dynamics study
Name
(type = personal)
NamePart
(type = family)
Narayanan
NamePart
(type = given)
Chitra
NamePart
(type = date)
1981-
DisplayForm
Chitra Narayanan
Role
RoleTerm
(authority = RULIB)
author
Name
(type = personal)
NamePart
(type = family)
Levy
NamePart
(type = given)
Ronald M
DisplayForm
Ronald M Levy
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
chair
Name
(type = personal)
NamePart
(type = family)
Baum
NamePart
(type = given)
Jean
DisplayForm
Jean Baum
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Nanda
NamePart
(type = given)
Vikas
DisplayForm
Vikas Nanda
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Gallicchio
NamePart
(type = given)
Emilio
DisplayForm
Emilio Gallicchio
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
outside member
Name
(type = corporate)
NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
(type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm
(authority = RULIB)
school
TypeOfResource
Text
Genre
(authority = marcgt)
theses
OriginInfo
DateCreated
(qualifier = exact)
2012
DateOther
(qualifier = exact);
(type = degree)
2012-10
Place
PlaceTerm
(type = code)
xx
Language
LanguageTerm
(authority = ISO639-2b);
(type = code)
eng
Subject
(authority = RUETD)
Topic
Biochemistry
RelatedItem
(type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
(type = RULIB)
ETD
Identifier
ETD_4247
PhysicalDescription
Form
(authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
xi, 120 p. : ill.
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Note
(type = vita)
Includes vita
Note
(type = statement of responsibility)
by Chitra Narayanan
Abstract
(type = abstract)
Proteins in their functional forms play a vital role in all major processes in the cell.
Protein misfolding has been associated with a large number of diseased states.
Intrinsically Disordered Proteins (IDPs) have gained much attention because of their
involvement in key cellular processes and predominance in diseased states. A number of
neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s
diseases have been correlated with the aggregation of IDPs.
α-synuclein is a 140 amino acid archetypal IDP implicated in the pathology of
Parkinson's disease. Aggregation of α-synuclein is sensitive to changes in amino acid
substitutions along the sequence and changes in chemical environments. Characterizing
the monomeric form is essential to understanding the conformational changes leading to
the aggregated state. In this work, ensembles of structures generated from Replica
Exchange Molecular Dynamics simulations were used to characterize aggregation-prone
states of monomeric form of α-synuclein.
The conformational characteristics of α-synuclein were evaluated in terms of the
statistical properties of the chain over a range of solvent conditions and comparing with
predictions from polymer theory, using temperature as a proxy for solvent quality.
Results of this work indicate that α-synuclein behaves as expected for a homopolymer
chain at extremes of solvent quality while at intermediate values, the identity of the
monomeric units along the sequence significantly influence the polymeric and
conformational characteristics of the chain. Comparison of the back-calculated
experimental parameters for the simulation ensemble with that of the NMR observation
shows that ensembles that fit to experimental parameters describing both local and longrange
characteristics, represented by the experimental Residual Dipolar Couplings (RDC)
and Paramagnetic Relaxation Enhancements respectively, provides a better representation
of the experimental ensemble.
The conformations of the neutral and low pH ensembles of α-synuclein were
characterized by integrating molecular simulations with experimental NMR observations,
to elucidate the effect of the altered charge distribution with change in pH on the
structural properties of these ensembles. The results from this study indicate a significant
structural reorganization with change in pH in terms of the long-range interactions,
compaction of the C-terminal region at low pH leading to faster aggregation at low pH.
Protein misfolding has been associated with a large number of diseased states.
Intrinsically Disordered Proteins (IDPs) have gained much attention because of their
involvement in key cellular processes and predominance in diseased states. A number of
neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s
diseases have been correlated with the aggregation of IDPs.
α-synuclein is a 140 amino acid archetypal IDP implicated in the pathology of
Parkinson's disease. Aggregation of α-synuclein is sensitive to changes in amino acid
substitutions along the sequence and changes in chemical environments. Characterizing
the monomeric form is essential to understanding the conformational changes leading to
the aggregated state. In this work, ensembles of structures generated from Replica
Exchange Molecular Dynamics simulations were used to characterize aggregation-prone
states of monomeric form of α-synuclein.
The conformational characteristics of α-synuclein were evaluated in terms of the
statistical properties of the chain over a range of solvent conditions and comparing with
predictions from polymer theory, using temperature as a proxy for solvent quality.
Results of this work indicate that α-synuclein behaves as expected for a homopolymer
chain at extremes of solvent quality while at intermediate values, the identity of the
monomeric units along the sequence significantly influence the polymeric and
conformational characteristics of the chain. Comparison of the back-calculated
experimental parameters for the simulation ensemble with that of the NMR observation
shows that ensembles that fit to experimental parameters describing both local and longrange
characteristics, represented by the experimental Residual Dipolar Couplings (RDC)
and Paramagnetic Relaxation Enhancements respectively, provides a better representation
of the experimental ensemble.
The conformations of the neutral and low pH ensembles of α-synuclein were
characterized by integrating molecular simulations with experimental NMR observations,
to elucidate the effect of the altered charge distribution with change in pH on the
structural properties of these ensembles. The results from this study indicate a significant
structural reorganization with change in pH in terms of the long-range interactions,
compaction of the C-terminal region at low pH leading to faster aggregation at low pH.
Subject
(authority = ETD-LCSH)
Topic
Protein folding
Subject
(authority = ETD-LCSH)
Topic
Amino acids--Metabolism--Disorders
Subject
(authority = ETD-LCSH)
Topic
Nervous system--Degeneration
Identifier
(type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000067078
RelatedItem
(type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
(type = local)
rucore19991600001
Location
PhysicalLocation
(authority = marcorg);
(displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier
(type = doi)
doi:10.7282/T33J3BPS
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
Narayanan
GivenName
Chitra
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = start)
2012-09-18 11:53:08
AssociatedEntity
Name
Chitra Narayanan
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
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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8872960
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8878080
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