Allosteric Modulation of Human Hsp90α Conformational Dynamics:
- Penkler, David L, Atilgan, Canan, Tastan Bishop, Özlem
- Authors: Penkler, David L , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162936 , vital:40998 , https://doi.org/10.1021/acs.jcim.7b00630
- Description: Central to Hsp90’s biological function is its ability to interconvert between various conformational states. Drug targeting of Hsp90’s regulatory mechanisms, including its modulation by cochaperone association, presents as an attractive therapeutic strategy for Hsp90 associated pathologies. In this study, we utilized homology modeling techniques to calculate full-length structures of human Hsp90α in closed and partially open conformations and used these structures as a basis for several molecular dynamics based analyses aimed at elucidating allosteric mechanisms and modulation sites in human Hsp90α.
- Full Text:
- Date Issued: 2018
- Authors: Penkler, David L , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162936 , vital:40998 , https://doi.org/10.1021/acs.jcim.7b00630
- Description: Central to Hsp90’s biological function is its ability to interconvert between various conformational states. Drug targeting of Hsp90’s regulatory mechanisms, including its modulation by cochaperone association, presents as an attractive therapeutic strategy for Hsp90 associated pathologies. In this study, we utilized homology modeling techniques to calculate full-length structures of human Hsp90α in closed and partially open conformations and used these structures as a basis for several molecular dynamics based analyses aimed at elucidating allosteric mechanisms and modulation sites in human Hsp90α.
- Full Text:
- Date Issued: 2018
MODE-TASK: Large-scale protein motion tools
- Ross, Caroline J, Nizami, B, Glenister, Michael, Sheik Amamuddy, Olivier, Atilgan, Ali R, Atilgan, Canan, Tastan Bishop, Özlem
- Authors: Ross, Caroline J , Nizami, B , Glenister, Michael , Sheik Amamuddy, Olivier , Atilgan, Ali R , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125206 , vital:35746 , http://dx.doi.org/10.1101/217505
- Description: Conventional analysis of molecular dynamics (MD) trajectories may not identify global motions of macromolecules. Normal Mode Analysis (NMA) and Principle Component Analysis (PCA) are two popular methods to quantify large-scale motions, and find the “essential motions”; and have been applied to problems such as drug resistant mutations (Nizami et al., 2016) and viral capsid expansion (Hsieh et al., 2016). MODE-TASK is an array of tools to analyse and compare protein dynamics obtained from MD simulations and/or coarse grained elastic network models. Users may perform standard PCA, kernel and incremental PCA (IPCA). Data reduction techniques (Multidimensional Scaling (MDS) and t-Distributed Stochastics Neighbor Embedding (t-SNE)) are implemented. Users may analyse normal modes by constructing elastic network models (ENMs) of a protein complex. A novel coarse graining approach extends its application to large biological assemblies.
- Full Text:
- Date Issued: 2018
- Authors: Ross, Caroline J , Nizami, B , Glenister, Michael , Sheik Amamuddy, Olivier , Atilgan, Ali R , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125206 , vital:35746 , http://dx.doi.org/10.1101/217505
- Description: Conventional analysis of molecular dynamics (MD) trajectories may not identify global motions of macromolecules. Normal Mode Analysis (NMA) and Principle Component Analysis (PCA) are two popular methods to quantify large-scale motions, and find the “essential motions”; and have been applied to problems such as drug resistant mutations (Nizami et al., 2016) and viral capsid expansion (Hsieh et al., 2016). MODE-TASK is an array of tools to analyse and compare protein dynamics obtained from MD simulations and/or coarse grained elastic network models. Users may perform standard PCA, kernel and incremental PCA (IPCA). Data reduction techniques (Multidimensional Scaling (MDS) and t-Distributed Stochastics Neighbor Embedding (t-SNE)) are implemented. Users may analyse normal modes by constructing elastic network models (ENMs) of a protein complex. A novel coarse graining approach extends its application to large biological assemblies.
- Full Text:
- Date Issued: 2018
Unraveling the Motions behind Enterovirus 71 Uncoating:
- Ross, Caroline J, Atilgan, Ali R, Tastan Bishop, Özlem, Atilgan, Canan
- Authors: Ross, Caroline J , Atilgan, Ali R , Tastan Bishop, Özlem , Atilgan, Canan
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148158 , vital:38715 , DOI: 10.1016/j.bpj.2017.12.021
- Description: Enterovirus 71 can be a severe pathogen in small children and immunocompromised adults. Virus uncoating is a critical step in the infection of the host cell; however, the mechanisms that control this process remain poorly understood. We applied normal mode analysis and perturbation response scanning to several complexes of the virus capsid and present a coarse-graining approach to analyze the full capsid. We show that our method offers an alternative to expressing the system as a set of rigid blocks and accounts for the interconnection between nodes within each subunit and protein interfaces across the capsid. In our coarse-grained approach, the modes associated with capsid expansion are captured in the first three nondegenerate modes and correspond to the changes observed in structural studies of the virus. We show that the resolution of the analysis may be modified without losing information on the global motions leading to uncoating.
- Full Text:
- Date Issued: 2018
- Authors: Ross, Caroline J , Atilgan, Ali R , Tastan Bishop, Özlem , Atilgan, Canan
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148158 , vital:38715 , DOI: 10.1016/j.bpj.2017.12.021
- Description: Enterovirus 71 can be a severe pathogen in small children and immunocompromised adults. Virus uncoating is a critical step in the infection of the host cell; however, the mechanisms that control this process remain poorly understood. We applied normal mode analysis and perturbation response scanning to several complexes of the virus capsid and present a coarse-graining approach to analyze the full capsid. We show that our method offers an alternative to expressing the system as a set of rigid blocks and accounts for the interconnection between nodes within each subunit and protein interfaces across the capsid. In our coarse-grained approach, the modes associated with capsid expansion are captured in the first three nondegenerate modes and correspond to the changes observed in structural studies of the virus. We show that the resolution of the analysis may be modified without losing information on the global motions leading to uncoating.
- Full Text:
- Date Issued: 2018
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