Date of Award

January 2016

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Kathryn Thomasson

Abstract

Among the physical methods available for studying protein structures, CD stands out as a property that is easy to measure yet remarkably difficult to predict theoretically. The basic principle underlying the CD of polypeptides and proteins is reasonably understood: the mixing of electronic transitions of monomer groups in the context of a chiral environment of helices gives rise to transitions that are both electronically and magnetically allowed. Despite knowledge on the fundamentals of CD, accurate theoretical prediction is still a major challenge. A better theoretical understanding of protein CD would facilitate a fuller interpretation of protein CD experiments.

Extensive theoretical studies have been conducted with some success to predict the CD spectra of polypeptides and proteins. One of such theoretical studies has been with the dipole interaction model, pioneered by J. Applequist. In this model, atoms and chromophores are considered to be point dipole oscillators that interact through mutually induced dipole moments in the presences of an electric field. The dipole interaction model has been assembled into a package (DInaMo) and used to successfully predict the far-UV CD of peptides and proteins. The major limitation of the method has been the neglect of the n-π* transition, and having to deal with a number of parameters, since no single parameter at the moment succeeds with all the different classes of proteins. Herein, in an attempt to improve the far-UV protein CD prediction capability of DInaMo, a number of issues are addressed: (1) Will the predicted CD be improved if mean polarizability values are used? (2) Since excluding methyl hydrogens on the amino acid residues have been successful, what happens if methylene and methylidyne hydrogens are also excluded? (3) How will the predicted spectrum differ upon addition of the n-π* amide transition? To answer these questions, a cyclic peptide (cyclo-(Gly-Pro-Gyl-D-Ala-Pro)) rebuilt with idealized bond angles and lengths, and a set of α-helical proteins obtained from the Protein Data Bank are energy minimized to adjust bond lengths and bond angles. The energy-minimized structures are then used to generate CD spectra with DInaMo. Mean polarizability parameters for methyl, methylene and methylidyne groups are developed and implemented on the cyclic peptide and protein. In addition, the effects of excluding methyl, methylene, and methylidyne hydrogens are investigated. Lastly, the n-π* transition is included in the predictions of α-helical proteins and peptides CD. Calculations using new mean polarizability parameters remove the need for different π-π* transition parameters and improve the CD results in lower RMSDs and better spectra morphology. Excluding more hydrogens improve results with larger protein. In addition, the n-π* transition parameters yield normal modes in the correct region and sign for this transition.

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