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Predicting the effect of genetic variance on the sequence-ensemble relationship of intrinsically disordered proteins

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TitleInfo
Title
Predicting the effect of genetic variance on the sequence-ensemble relationship of intrinsically disordered proteins
Name (type = personal)
NamePart (type = family)
Lohia
NamePart (type = given)
Ruchi
NamePart (type = date)
1991-
DisplayForm
Ruchi Lohia
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Brannigan
NamePart (type = given)
Grace
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Grace Brannigan
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Fu
NamePart (type = given)
Jinglin
DisplayForm
Jinglin Fu
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Klein
NamePart (type = given)
Eric
DisplayForm
Eric Klein
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Abrams
NamePart (type = given)
Cameron
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Cameron Abrams
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
Camden Graduate School
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
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2019
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2019-10
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2019
Language
LanguageTerm (authority = ISO 639-3:2007); (type = text)
English
Abstract (type = abstract)
A hierarchical sequence-based framework for analysis and conceptualization of intrinsically disordered proteins (IDPs) is presented. This framework was further used to develop a novel test for enrichment of higher-order (tertiary) structure in a disordered protein using Molecular Dynamics (MD) simulations and Monte Carlo simulations. Finally, we show that the developed framework can also serve as a useful tool in predicting the consequence of an amino acid substitution on the IDPs function using a bioinformatics approach.
In structured proteins, contacts between residues distant along the sequence are reflected in the tertiary structure, but developing a framework for describing the analogous property in IDPs has not been straightforward. The distribution of hydrophobic residues within the sequence was used to identify 4-15 residues `blobs' representing local globular regions or linkers. We use this framework within a novel test for enrichment of higher-order (tertiary) structure in disordered proteins; the size and shape of each blob is extracted from MD simulation of the real protein (RP) and used to parameterize a self-avoiding heterogeneous polymer (SAHP). In our study on the 91-residue disordered prodomain of brain derived neurotrophic factor (BDNF), we find that the long 15 residue linker itself creates a segmentation in contact pair map for both SAHP and RP. We find that in RP only the contact between the segmented region is enriched relative to SAHP. We further quantified the enrichment observed for several other hydrophobic substitutions within the disordered prodomain, including the disease-causing Val66Met substitution. We find that in RPs the enrichment observed in the contact between the segmented region is sensitive to amino acid substitution as well. Only the disease-associated Met66 substitution enriches these contacts significantly, due to a preferred Met-Met interaction. Furthermore, we find several properties of the blobs identified with the sequence-based framework which are enriched in disease-associated SNPs relative to non disease-associated SNPs. This allowed us to present the first systematic, bottom-up, attempt to both identify and annotate subdomains within disordered proteins that are enriched for functional effects.
Subject (authority = RUETD)
Topic
Computational and Integrative Biology
Subject (authority = LCSH)
Topic
Proteins -- Genetics
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_10272
PhysicalDescription
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application/pdf
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text/xml
Extent
1 online resource (xiii, 113 pages) : illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
RelatedItem (type = host)
TitleInfo
Title
Camden Graduate School Electronic Theses and Dissertations
Identifier (type = local)
rucore10005600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/t3-00rt-0w08
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
Lohia
GivenName
Ruchi
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2019-09-19 15:34:51
AssociatedEntity
Name
Ruchi Lohia
Role
Copyright holder
Affiliation
Rutgers University. Camden Graduate School
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.
RightsEvent
Type
Embargo
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2019-10-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2020-10-30
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 30th, 2020.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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2019-09-24T16:27:10
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2019-09-24T16:27:10
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