Correlated long-distance dynamics modulate monoclonal antibody binding resistance in flaviviral envelope pretein domain-3: A molecular dynamics simulations study

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dc.contributor.advisorDr. Stanley J. Watowichen_US
dc.contributor.committeeMemberDr. Marion L. Dodsonen_US
dc.contributor.committeeMemberDr. Alan D. Barretten_US
dc.contributor.committeeMemberDr. James C. Leeen_US
dc.creatorkeerthi gottipatien_US
dc.date.accessioned2011-12-20T16:05:39Z
dc.date.available2008-12-10en_US
dc.date.available2011-12-20T16:05:39Z
dc.date.created2008-12-01en_US
dc.date.issued2008-11-21en_US
dc.description.abstractNumerous monoclonal antibody (MAb) binding resistant mutations have been localized to the envelope protein domain-3 (ED3) of flaviviruses. Previously it was shown that regions constituting antibody binding sites of dengue-2 (DEN2) and West Nile virus (WNV) ED3 were energetically coupled with the interior of the protein. Protein-protein interactions are characterized by perturbation of residue dynamics at the binding interface and at regions physically far from the binding site. Based on above I hypothesized that mutations leading to resistance from antibody binding would perturb dynamics associated with binding at the interface and therefore also the correlation in motions with the interior of the protein. I investigated this hypothesis by analyzing the dynamics of wild type and mutant ED3s of DEN2 and WNV using molecular dynamics (MD) simulations and principal components analysis (PCA). I found that residues constituting binding sites for the MAbs, when mutated, drastically perturb the organized motions in the peptide. Cross-correlation analysis of the dynamics established that the MAb binding resistant mutations perturbed correlated long distance dynamics globally. Computationally this analysis aids in locating the MAb binding regions in flaviviral ED3s through simple analysis wild type and mutant MD trajectories.en_US
dc.format.mediumelectronicen_US
dc.identifier.otheretd-12012008-101003en_US
dc.identifier.urihttp://hdl.handle.net/2152.3/277
dc.language.isoengen_US
dc.rightsCopyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.en_US
dc.subjectprotein-dynamicsen_US
dc.subjectMD-simulationsen_US
dc.subjectlong-distance communicationen_US
dc.subjectflavivirusen_US
dc.subjectenvelope proteinen_US
dc.subjectdomain-3en_US
dc.titleCorrelated long-distance dynamics modulate monoclonal antibody binding resistance in flaviviral envelope pretein domain-3: A molecular dynamics simulations studyen_US
dc.type.genrethesisen_US
dc.type.materialtexten_US
thesis.degree.departmentBiochemistry and Molecular Biologyen_US
thesis.degree.grantorThe University of Texas Medical Branchen_US
thesis.degree.levelMasteren_US
thesis.degree.nameMaster of Scienceen_US

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