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A multiscale computational approach to study RNase A catalysis

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TitleInfo
Title
A multiscale computational approach to study RNase A catalysis
Name (type = personal)
NamePart (type = family)
Dissanayake Rallage
NamePart (type = given)
Thakshila D.
NamePart (type = date)
1981-
DisplayForm
Thakshila D. Dissanayake Rallage
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
York
NamePart (type = given)
Darrin M
DisplayForm
Darrin M York
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Case
NamePart (type = given)
David A
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David A Case
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)
Jha
NamePart (type = given)
Shantenu
DisplayForm
Shantenu Jha
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 (encoding = w3cdtf); (qualifier = exact)
2016
DateOther (qualifier = exact); (type = degree)
2016-01
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2016
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Enzyme catalysis is an extremely important and complex process that is fundamental to biology. Experiments provide a wealth of valuable information about the function of enzymes; however, this information requires the use of computational models to establish a meaningful interpretation that can be used to guide design. Multiscale computational models, which integrate a hierarchy of theoretical methods to address complex biomolecular problems that span large spatial and temporal ranges, afford powerful tools to provide a detailed molecular level interpretation of a wide range of experimental data from which a consensus view of catalytic mechanism may emerge. In this dissertation, I detail my efforts to develop and apply multiscale methods to study the mechanisms of RNA backbone cleavage catalyzed by Ribonuclease A, an important archetype enzyme system, and the factors that regulate its activity. In the first phase of this research, I use molecular dynamics simulations to characterize the structure and dynamics of the active enzyme in solution at different stages along the reaction path. In this work, I demonstrate that the crystallographic structure represents an inactive, catalytically non-relevant state, and make predictions that a conformational change involving the flipping of the side chain of a conserved histidine residue (His12) is required to adopt a catalytically competent conformation. In the second phase of this research, I apply ''constant pH molecular dynamics simulations'' (CpHMD) to characterize the conditional probability of finding key active site residues in a protonation state that supports general acid-base catalysis. This allowed the prediction of pKa shifts for His12, His119 and Lys41, and, for the first time, activity-pH profiles for an enzyme system that can be compared directly with those measured in kinetic experiments. In the third phase of this research, I use combined quantum mechanical/molecular mechanical methods to study the catalytic chemical steps of transphosphorylation. Results of this work predict a free energy landscape for the reaction, from which the minimum free energy pathway that connects reactants and products allows a detailed molecular-level picture of mechanism. In the fourth phase of this research, I extend the CpHMD method to nucleic acid systems, to benchmark the method for the study of ribozymes that catalyze the same reaction as RNase A.
Subject (authority = RUETD)
Topic
Computational Biology and Molecular Biophysics
Subject (authority = ETD-LCSH)
Topic
Ribonucleases
Subject (authority = ETD-LCSH)
Topic
Catalysts
Subject (authority = ETD-LCSH)
Topic
RNA
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_6935
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xx, 124 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Thakshila D. Dissanayake Rallage
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/T3MC922M
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
Dissanayake Rallage
GivenName
Thakshila
MiddleName
D.
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2015-12-20 22:08:30
AssociatedEntity
Name
Thakshila Dissanayake Rallage
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.
RightsEvent
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2016-01-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2018-01-30
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after January 30th, 2018.
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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