자료유형  

 학위논문

Control Number  

0016931999

International Standard Book Number  

9798379650551

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Fakharzadeh-Ghaan, Ashkan.

Publication, Distribution, etc. (Imprint  

[S.l.] : North Carolina State University., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(321 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 84-12, Section: B.

General Note  

Advisor: Riehn, Robert;Rose, Robert B.;Sagui, Maria;Roland, Christopher.

Dissertation Note  

Thesis (Ph.D.)--North Carolina State University, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Atypical DNA secondary structures have been identified as a common and causative factor for simple sequence repeat expansion, which underpins approximately fifty DNA trinucleotide repeat (TR) neurodegenerative and neuromuscular diseases. These types of triplets are the most common type of simple sequence repeat found in all known eukaryotic genomes' exomes. TRs may cause defects in a protein encoded by a gene, alter gene expression regulation, produce toxic RNA, or cause chromosome instability, depending on their location. Intergenerational repeat expansions exhibit genetic anticipation, whereas somatic expansions are causing disease progression. Although it is well known that repeat length and atypical non-B DNA stable secondary structures are two main factors behind TR disorders, less is known about the molecular details of the atypical structures. In this thesis, we have used classical molecular dynamics simulations, with state-of-the-art force fields and sampling methods to study conformational characteristics and the free energy landscape of several alternative nucleic acid structures.First, we studied DNA triplexes and RNA/DNA hybrids associated with GAA/TTC trinucleotide repeats found in the first intron of the frataxin (FXN) gene causing Friedreich's ataxia (FRDA). Using large scale molecular dynamics simulations, we have explored the 16 possible DNA triplexes that can be formed from these GAA/TTC repeats, as well as the two hybrid RNA:DNA helical duplexes and three possible DNA.DNA:RNA triplexes that can form a collapsed R-loop. We explored the stability of these triplex structures and found for TTC.GAA:TTC triple helices, the third TTC strand in parallel alignment with bases in an anti conformation is the most stable; for GAA.GAA:TTC triple helices, the GAA third strand in parallel alignment with bases in an anti conformation along with two protonated cases are the most stable. With regards to hybrid RNA:DNA helices, our structural analysis indicates that r(GAA):d(TTC) is more stable and closer to A-RNA than d(GAA):r(UUC) which directly impacts the stability of the resulting triplex, i.e. d(TTC+ )·d(GAA):r(UUC) is unstable while d(GAA)·r(GAA):d(TTC) and d(GA+A)·r(GAA):d(TTC) are stable. We expanded our study to all possible triplexes that form by attaching a third RNA strand to an RNA:RNA or DNA:DNA duplex assembled from GAA and TTC or UUC sequences. For both new triplexes results are similar. For a pyrimidine UUC+ third strand, the parallel orientation is stable while its antiparallel counterpart is unstable. For a neutral GAA third strand, the parallel conformation is stable. A protonated GA+A third strand is stable in both parallel and antiparallel orientations. We have also investigated Na+ and Mg2+ ion distributions around the triplexes.Then, we targeted DNA duplexes with GGC and CGG sequence with GG mismatches TRs in Z-form and DNA/RNA duplexes with CTG/CUG and GTC/GUC repeats in B-from as well as CAG:CTG (or CUG), CUG:CTG, and GUC:GTC hybrid double helices. Extended repeats of CGG/GGC TRs in the pathological range leads to male fragile X-associated tremor ataxia syndrome (FXTAS), premature ovarian failure, inherited fragile X mental retardation syndrome as well as Baratela-Scott syndrome. The experiments were not able to reveal the actual molecular conformation of this yet unknown CGG TR motif.

Subject Added Entry-Topical Term  

RNA polymerase.

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Hydrogen bonds.

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Sampling techniques.

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Handedness.

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Genetic disorders.

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Disease.

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Binding sites.

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Maps.

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Deoxyribonucleic acid--DNA.

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Genomes.

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Energy.

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Ataxia.

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Biochemistry.

Subject Added Entry-Topical Term  

Genetics.

Added Entry-Corporate Name  

North Carolina State University.

Host Item Entry  

Dissertations Abstracts International. 84-12B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:640762