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Nucleic Acid Structure and Interactions Revealed by Computer Simulations.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Nucleic Acid Structure and Interactions Revealed by Computer Simulations./
作者:	He, Weiwei.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
面頁冊數:	507 p.
附註:	Source: Dissertations Abstracts International, Volume: 85-04, Section: B.
Contained By:	Dissertations Abstracts International85-04B.
標題:	Computational chemistry. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30631045
ISBN:	9798380622509

Nucleic Acid Structure and Interactions Revealed by Computer Simulations.
He, Weiwei.

Nucleic Acid Structure and Interactions Revealed by Computer Simulations. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 507 p.

Source: Dissertations Abstracts International, Volume: 85-04, Section: B.

Thesis (Ph.D.)--New York University, 2023.

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

Many fundamental cellular processes, such as genome packaging and phase separation, involve nucleic acids (NAs) that is essential to all known forms of life. The functional and therapeutic roles played by NAs biopolymers are intimately linked to their structural-dynamic properties. Hence, there is a keen interest to advance the determination of the atomic-level structural dynamics of NAs in physiological conditions and construct high-resolution models of their structures. Despite significant progress, it remains challenging for either experimental or computational techniques alone to accurately resolve the structural ensembles of NAs molecules and their interactions with biomolecular counterparts in atomic detail. This dissertation presents my graduate research, which focuses on developing new integrated methods to tackle these challenges and elucidate the structures and interactions of DNA and RNA through the synergy of experiments and atomistic simulations.Our results demonstrate that strong attraction of double-stranded DNA (dsDNA) is facilitated by the correlated dynamics of localized cations at the grooves of DNA helices, leading to sequence-dependent orientational coupling and electrostatic attraction, and strongly depends on salt conditions and DNA sequences. The condensation of double-stranded RNA (dsRNA) adopts a different mechanism, where the loss of translational and rotational entropy on RNA duplexes plays a vital role. (Chapter 2, 3) Furthermore, we demonstrate that divalent metal ions interact with the negatively charged phosphate groups of lipid headgroups and DNA, tethering DNA to the membrane surface and inducing DNA condensation within membrane bilayers. (Chapter 4)We also study the structural properties of a variety of DNA and RNA structures via the integration of all-atom MD simulations and experiments, such as solution X-ray scattering and FRET. Depending on the nature of the biopolymer and experimental condition, we implement different approaches, including data-driven sampling and ensemble reweighting. We show the robust correlations between features in the scattering profiles and real-space geometries of biomolecules. We observe that dsDNA exhibits sequence dependence while dsRNA displays a marked sensitivity to the salt conditions. (Chapter 5) We also analyze the structure of RNA triple helices and describe the conformational variations in the dsRNA at the major groove upon the incorporation of a third strand by base-triples. (Chapter 6) In addition, we solve the solution structures of SARS-CoV-2 pseudoknot RNA and its a point mutant, and observe that the pseudoknot molecule adopts a bent conformation and exhibits marked structural heterogeneity in solution, with the mutant displaying a notably more bent structure with reoriented helices. We also explore their mechanical properties. The free energy profiles along the mechanical reaction coordinate demonstrate that a point mutation on the pseudoknot significantly enhances its mechanical stability.(Chapter 7)Moreover, we research RNA molecules that exhibit structural heterogeneity and/or are sensitive to ligand binding. We observe that two-way junction RNA (HJH) is highly sensitive to ionic strength variations in solution, and we report on a dynamic change of the SAM-I riboswitch conformations depending on its binding partners. (Chapter 8) In addition, the structural-dynamics properties of disordered single-stranded RNA (ssRNA) are investigated. This study demonstrates that 'disorder' does not mean random, and that heteropolymer ssRNA exhibits structural features, such as pronounced helicity, distinct from homopolymer ssRNA. (Chapter 9)Finally, we describe our novel strategies for optimizing RNA force fields against small-angle X-ray scattering using RNA HJH as the model. We show that refining hydrogen bonding, backbone, and base stacking parameters balance the forces governing RNA folding. And the modified RNA force field (HB-CUFIX) demonstrates improved performance in studying thermodynamics and structural properties of realistic RNA motifs. (Chapter 10).

ISBN: 9798380622509Subjects--Topical Terms:

3350019
Computational chemistry.
Subjects--Index Terms:

DNA

Nucleic Acid Structure and Interactions Revealed by Computer Simulations.
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245 1 0 $a Nucleic Acid Structure and Interactions Revealed by Computer Simulations.
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300 $a 507 p.
500 $a Source: Dissertations Abstracts International, Volume: 85-04, Section: B.
500 $a Advisor: Kirmizialtin, Serdal.
502 $a Thesis (Ph.D.)--New York University, 2023.
506 $a This item must not be sold to any third party vendors.
520 $a Many fundamental cellular processes, such as genome packaging and phase separation, involve nucleic acids (NAs) that is essential to all known forms of life. The functional and therapeutic roles played by NAs biopolymers are intimately linked to their structural-dynamic properties. Hence, there is a keen interest to advance the determination of the atomic-level structural dynamics of NAs in physiological conditions and construct high-resolution models of their structures. Despite significant progress, it remains challenging for either experimental or computational techniques alone to accurately resolve the structural ensembles of NAs molecules and their interactions with biomolecular counterparts in atomic detail. This dissertation presents my graduate research, which focuses on developing new integrated methods to tackle these challenges and elucidate the structures and interactions of DNA and RNA through the synergy of experiments and atomistic simulations.Our results demonstrate that strong attraction of double-stranded DNA (dsDNA) is facilitated by the correlated dynamics of localized cations at the grooves of DNA helices, leading to sequence-dependent orientational coupling and electrostatic attraction, and strongly depends on salt conditions and DNA sequences. The condensation of double-stranded RNA (dsRNA) adopts a different mechanism, where the loss of translational and rotational entropy on RNA duplexes plays a vital role. (Chapter 2, 3) Furthermore, we demonstrate that divalent metal ions interact with the negatively charged phosphate groups of lipid headgroups and DNA, tethering DNA to the membrane surface and inducing DNA condensation within membrane bilayers. (Chapter 4)We also study the structural properties of a variety of DNA and RNA structures via the integration of all-atom MD simulations and experiments, such as solution X-ray scattering and FRET. Depending on the nature of the biopolymer and experimental condition, we implement different approaches, including data-driven sampling and ensemble reweighting. We show the robust correlations between features in the scattering profiles and real-space geometries of biomolecules. We observe that dsDNA exhibits sequence dependence while dsRNA displays a marked sensitivity to the salt conditions. (Chapter 5) We also analyze the structure of RNA triple helices and describe the conformational variations in the dsRNA at the major groove upon the incorporation of a third strand by base-triples. (Chapter 6) In addition, we solve the solution structures of SARS-CoV-2 pseudoknot RNA and its a point mutant, and observe that the pseudoknot molecule adopts a bent conformation and exhibits marked structural heterogeneity in solution, with the mutant displaying a notably more bent structure with reoriented helices. We also explore their mechanical properties. The free energy profiles along the mechanical reaction coordinate demonstrate that a point mutation on the pseudoknot significantly enhances its mechanical stability.(Chapter 7)Moreover, we research RNA molecules that exhibit structural heterogeneity and/or are sensitive to ligand binding. We observe that two-way junction RNA (HJH) is highly sensitive to ionic strength variations in solution, and we report on a dynamic change of the SAM-I riboswitch conformations depending on its binding partners. (Chapter 8) In addition, the structural-dynamics properties of disordered single-stranded RNA (ssRNA) are investigated. This study demonstrates that 'disorder' does not mean random, and that heteropolymer ssRNA exhibits structural features, such as pronounced helicity, distinct from homopolymer ssRNA. (Chapter 9)Finally, we describe our novel strategies for optimizing RNA force fields against small-angle X-ray scattering using RNA HJH as the model. We show that refining hydrogen bonding, backbone, and base stacking parameters balance the forces governing RNA folding. And the modified RNA force field (HB-CUFIX) demonstrates improved performance in studying thermodynamics and structural properties of realistic RNA motifs. (Chapter 10).
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