ingest cdrApp 2017-07-05T13:10:09.456Z 5f66f245-eb3d-4dc8-9ba0-36f1d138d2ac modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-07-05T13:25:21.983Z Setting exclusive relation modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-07-05T13:25:30.164Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2017-07-05T13:25:38.142Z Adding technical metadata derived by FITS modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-07-05T13:25:57.407Z Setting exclusive relation addDatastream MD_FULL_TEXT fedoraAdmin 2017-07-05T13:26:06.315Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-07-05T13:26:22.204Z Setting exclusive relation modifyDatastreamByValue RELS-EXT cdrApp 2017-07-05T17:51:48.086Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-25T05:19:27.176Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-27T05:54:42.443Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-03-14T02:00:59.883Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-05-17T13:56:42.296Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-11T00:30:44.206Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-17T20:30:02.019Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-08T19:57:09.224Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-15T17:06:00.641Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-16T20:08:35.569Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-21T17:33:31.287Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-26T20:51:45.177Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-10-11T21:22:50.956Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-20T14:46:40.750Z Benfeard Williams Author Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. Spring 2017 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. Spring 2017 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. Spring 2017 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. 2017-05 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text 2017-05 Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text 2017-05 Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text 2017-05 Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text 2017-05 Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text 2017-05 University of North Carolina at Chapel Hill Degree granting institution Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text 2017-05 Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text 2017-05 Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. 2017 Biophysics Biochemistry alzheimer's disease; apolipoprotein e; molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text 2017-05 Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. 2017 Biophysics Biochemistry alzheimer's disease, apolipoprotein e, molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Biochemistry and Biophysics Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text 2017-05 Benfeard Williams Creator Department of Biochemistry and Biophysics School of Medicine Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics. 2017 Biophysics Biochemistry alzheimer's disease; apolipoprotein e; molecular dynamics eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Nikolay Dokholyan Thesis advisor Qi Zhang Thesis advisor Sharon Campbell Thesis advisor Todd Cohen Thesis advisor Ben Major Thesis advisor text 2017-05 Williams_unc_0153D_16743.pdf uuid:2c0f123e-e752-4c30-a8e5-dfc1f2b51562 2019-07-05T00:00:00 2017-04-22T15:42:16Z proquest application/pdf 104558248 yes