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Structure and Thermodynamics of Poly...

Workman, Riley J.

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Structure and Thermodynamics of Polyglutamine Peptides and Amyloid Fibrils via Metadynamics and Molecular Dynamics Simulations.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Structure and Thermodynamics of Polyglutamine Peptides and Amyloid Fibrils via Metadynamics and Molecular Dynamics Simulations./
作者:	Workman, Riley J.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	97 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-03, Section: B.
Contained By:	Dissertations Abstracts International80-03B.
標題:	Chemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10841592
ISBN:	9780438352001

Structure and Thermodynamics of Polyglutamine Peptides and Amyloid Fibrils via Metadynamics and Molecular Dynamics Simulations.
Workman, Riley J.

Structure and Thermodynamics of Polyglutamine Peptides and Amyloid Fibrils via Metadynamics and Molecular Dynamics Simulations. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 97 p.

Source: Dissertations Abstracts International, Volume: 80-03, Section: B.

Thesis (Ph.D.)--Duquesne University, 2018.

This item is not available from ProQuest Dissertations & Theses.

Aggregation of polyglutamine (polyQ)-rich polypeptides in neurons is a marker for nine neurodegenerative diseases. The molecular process responsible for the formation of polyQ fibrils is not well understood and represents a growing area of study. To enable development of treatments that could interfere with aggregation of polyQ peptides, it is crucial to understand the molecular mechanisms by which polyQ pep- tides aggregate into fibrils. Many experimental techniques have been employed to probe polyQ aggregation, however, observations from these studies have not lead to a unified understanding of the properties of these systems, instead yielding competing, fragmented theories of polyQ aggregation. This dissertation addresses these gaps in knowledge by shedding light on important steps of the aggregation process. The structural motif of polyQ fibrils is not agreed upon in the field, which is worrying, given that these structures are the endpoint of polyQ aggregation. Here, molecular dynamics (MD) simulations paired with UV resonance Raman (UVRR) experiments show that short polyQ peptides adopt extended antiparallel β-sheet fibrils, contrary to β-hairpin structures oft predicted in the polyQ field. The structure of monomeric polyQ peptides was then studied to gain insight into the beginnings of the aggregation mechanism. Metadynamics MD simulations were used to characterize the conformational energy landscape of polyQ peptides, and this data was compared to experimental UVRR results. We found short polyQ peptides can adopt PPII-rich and collapsed β-strand monomeric structures, which establishes that polyQ can form distinct conformational states as monomers. The effect of increased polyQ repeat length was also tested, and it was found that increased repeat length corresponds to lower energy barriers between monomeric conformational states, which may explain why longer polyQ repeats are quicker to aggregate. Hydrogen bonding strengths of polyQ monomers and fibrils were also investigated with MD and UVRR, showing that polyQ peptides favor intrapeptide hydrogen bonds over those between peptide and water. Overall, the work in this dissertation deepens the understanding of the polyQ aggregation mechanism by determining the structure and thermodynamics of monomeric and fibrillar states, as well as identifying polyQ peptide hydrogen bonding as one of the driving forces in these systems. This knowledge can aid the development of molecular mechanisms to interfere with the formation of toxic polyQ aggregates that trigger the onset of polyQ diseases.

ISBN: 9780438352001Subjects--Topical Terms:

516420
Chemistry.
Subjects--Index Terms:

Aggregation

Structure and Thermodynamics of Polyglutamine Peptides and Amyloid Fibrils via Metadynamics and Molecular Dynamics Simulations.
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245 1 0 $a Structure and Thermodynamics of Polyglutamine Peptides and Amyloid Fibrils via Metadynamics and Molecular Dynamics Simulations.
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300 $a 97 p.
500 $a Source: Dissertations Abstracts International, Volume: 80-03, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Evanseck, Jeffrey D.
502 $a Thesis (Ph.D.)--Duquesne University, 2018.
506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
520 $a Aggregation of polyglutamine (polyQ)-rich polypeptides in neurons is a marker for nine neurodegenerative diseases. The molecular process responsible for the formation of polyQ fibrils is not well understood and represents a growing area of study. To enable development of treatments that could interfere with aggregation of polyQ peptides, it is crucial to understand the molecular mechanisms by which polyQ pep- tides aggregate into fibrils. Many experimental techniques have been employed to probe polyQ aggregation, however, observations from these studies have not lead to a unified understanding of the properties of these systems, instead yielding competing, fragmented theories of polyQ aggregation. This dissertation addresses these gaps in knowledge by shedding light on important steps of the aggregation process. The structural motif of polyQ fibrils is not agreed upon in the field, which is worrying, given that these structures are the endpoint of polyQ aggregation. Here, molecular dynamics (MD) simulations paired with UV resonance Raman (UVRR) experiments show that short polyQ peptides adopt extended antiparallel β-sheet fibrils, contrary to β-hairpin structures oft predicted in the polyQ field. The structure of monomeric polyQ peptides was then studied to gain insight into the beginnings of the aggregation mechanism. Metadynamics MD simulations were used to characterize the conformational energy landscape of polyQ peptides, and this data was compared to experimental UVRR results. We found short polyQ peptides can adopt PPII-rich and collapsed β-strand monomeric structures, which establishes that polyQ can form distinct conformational states as monomers. The effect of increased polyQ repeat length was also tested, and it was found that increased repeat length corresponds to lower energy barriers between monomeric conformational states, which may explain why longer polyQ repeats are quicker to aggregate. Hydrogen bonding strengths of polyQ monomers and fibrils were also investigated with MD and UVRR, showing that polyQ peptides favor intrapeptide hydrogen bonds over those between peptide and water. Overall, the work in this dissertation deepens the understanding of the polyQ aggregation mechanism by determining the structure and thermodynamics of monomeric and fibrillar states, as well as identifying polyQ peptide hydrogen bonding as one of the driving forces in these systems. This knowledge can aid the development of molecular mechanisms to interfere with the formation of toxic polyQ aggregates that trigger the onset of polyQ diseases.
590 $a School code: 0067.
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650 4 $a Biophysics. $3 518360
653 $a Aggregation
653 $a Amyloid
653 $a Fibrils
653 $a Huntington's disease
653 $a Metadynamics
653 $a Polyglutamine
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690 $a 0786
710 2 $a Duquesne University. $b Chemistry and Biochemistry. $3 2098701
773 0 $t Dissertations Abstracts International $g 80-03B.
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