Show simple item record

dc.contributor.advisorHarvey, Stephen C.
dc.contributor.advisorMcCarty, Nael A.
dc.contributor.authorRahman, Kazi Shefaet
dc.date.accessioned2014-01-13T16:49:28Z
dc.date.available2014-01-13T16:49:28Z
dc.date.created2013-12
dc.date.issued2013-11-14
dc.date.submittedDecember 2013
dc.identifier.urihttp://hdl.handle.net/1853/50346
dc.description.abstractMutations 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.
dc.format.mimetypeapplication/pdf
dc.language.isoen_US
dc.publisherGeorgia Institute of Technology
dc.subjectCFTR
dc.subjectABC transporters
dc.subjectMolecular modeling
dc.subjectMolecular dynamics
dc.subjectHomology modeling
dc.subject.lcshCystic fibrosis
dc.subject.lcshCystic fibrosis gene
dc.subject.lcshATP-binding cassette transporters
dc.subject.lcshMembrane proteins
dc.titleMolecular modeling and simulations of the conformational changes underlying channel activity in CFTR
dc.typeDissertation
dc.description.degreePh.D.
dc.contributor.departmentBiomedical Engineering (Joint GT/Emory Department)
thesis.degree.levelDoctoral
dc.contributor.committeeMemberJordan, King
dc.contributor.committeeMemberLudovice, Peter J.
dc.contributor.committeeMemberZhu, Cheng
dc.date.updated2014-01-13T16:49:28Z


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record