学位论文详细信息
Molecular modeling and simulations of the conformational changes underlying channel activity in CFTR
CFTR;ABC transporters;Molecular modeling;Molecular dynamics;Homology modeling
Rahman, Kazi Shefaet ; Harvey, Stephen C. McCarty, Nael A. Biomedical Engineering (Joint GT/Emory Department) Jordan, King Ludovice, Peter J. Zhu, Cheng ; Harvey, Stephen C.
University:Georgia Institute of Technology
Department:Biomedical Engineering (Joint GT/Emory Department)
关键词: CFTR;    ABC transporters;    Molecular modeling;    Molecular dynamics;    Homology modeling;   
Others  :  https://smartech.gatech.edu/bitstream/1853/50346/1/RAHMAN-DISSERTATION-2013.pdf
美国|英语
来源: SMARTech Repository
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【 摘 要 】

Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) cause cystic fibrosis (CF), the most common life-shortening genetic disease among Caucasians. Although general features of the structure of CFTR have been predicted from homology models, the conformational changes that result in channel opening and closing have yet to be resolved. We created new closed- and open-state homology models of CFTR, and performed targeted molecular dynamics simulations of the conformational transitions in a channel opening event. The simulations predict a conformational wave that starts at the nucleotide binding domains and ends with the formation of an open conduction pathway. Experimentally confirmed changes in side-chain interactions are observed in all major domains of the protein. We also identified unique-to-CFTR substitutions that may have led to channel activity in CFTR. Molecular modeling and simulations are used to compare the effects of these substitutions against a canonical ABC transporter, and suggest that gain of channel function in CFTR may have risen from loss of ATPase function at its NBDs. The models and simulation add to our understanding of the mechanism of ATP-dependent gating in this disease-relevant ion channel.

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