Computer simulation of titration behavior in proteins

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biophysics and Computational Biology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2011

Author dc:creator

• Gibas, Cynthia Jeanne

Contributors dc:contributor

• Subramaniam, Shankar
• Wraight, Colin A.

• Chemistry, Biochemistry
• Biophysics, General

Statement dc:rights

• Copyright 1996 Gibas, Cynthia Jeanne

Language dc:language

eng

Identifier

9780591198225
AAI9712282
(UMI)AAI9712282

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/22269