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 Title: Computer simulation of titration behavior in proteins Author(s): Gibas, Cynthia Jeanne Doctoral Committee Chair(s): Subramaniam, Shankar; Wraight, Colin A. Department / Program: Biophysics and Computational Biology Discipline: Biophysics and Computational Biology Degree Granting Institution: University of Illinois at Urbana-Champaign Degree: Ph.D. Genre: Dissertation Subject(s): Chemistry, Biochemistry Biophysics, General Abstract: The pH dependent properties of proteins can be successfully modeled using continuum electrostatic methods provided that a sufficiently detailed and accurate model of the protein system is used. In this work, the effects of conformational changes on calculated pK$\rm\sb{a}$ values in peptide and protein systems are investigated, and it is found that an ensemble of structures may be the best representation of a protein to use for the calculation of pH-dependent properties. Studies of the effects of inclusion of explicit water molecules in the continuum electrostatic model show that this modification may improve results when an optimal number of water molecules is used. A modification to the continuum electrostatics-based multiple site titration theory based on solvent accessibility is proposed, and it is shown that this model results in improved agreement of calculated pK$\rm\sb{a}$ values with experiment when a low protein interior dielectric constant is used. The techniques developed are applied to two large protein systems. A trio of antibody/lysozyme complexes which differ minimally in epitope and paratope structure, but have widely varying association constants, are studied. In addition to electrostatic techniques, results of contact mapping and molecular surface area and volume calculations aid in the understanding of the differing properties of these systems. Several modeled mutant structures of each antibody and lysozyme are also examined. Each of these is predicted to associate less strongly with its counterpart than in the wild type. The photosynthetic reaction center of Rb. sphaeroides is studied, with some success in reproducing its known pH-dependent proton uptake. Mutants in which two critical residues in the secondary quinone binding site of the reaction center are altered are shown to be proton uptake impaired, with respect to the wild type. Issue Date: 1996 Type: Text Language: English URI: http://hdl.handle.net/2142/22269 ISBN: 9780591198225 Rights Information: Copyright 1996 Gibas, Cynthia Jeanne Date Available in IDEALS: 2011-05-07 Identifier in Online Catalog: AAI9712282 OCLC Identifier: (UMI)AAI9712282
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