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Thermodynamic and spectroscopic studies of metalloprotein stability ligation and reactivity / by George P. Lisi III.

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Call No.	QD47.5.N43 D3 2014lis
Author	Lisi, George P.
Title	Thermodynamic and spectroscopic studies of metalloprotein stability ligation and reactivity / by George P. Lisi III.
Date	2014
Abstract	Metal ions confer structural stability and reactivity to a large number of proteins that use the amino acids histidine (His) and cysteine (Cys) to form stable metal-ligand complexes. The stability of metal-His and metal-Cys interactions and their global effect on protein structure have been quantified using differential scanning calorimetry (DSC) and complementary spectroscopic methods. In the first study, the Zn??-containing enzyme carbonic anhydrase (CA), where the metal is coordinated by three His residues, the native Zn??-, and the Co??-,Cd??-,Cu??-,Ni??-, and Mn??-substituted enzymes are all more stable than the apo (metal-free) form, with the magnitude of the additional stability depending on the metal ion. DFT calculations reveal that constaints of the protein environment distort and destabilize the metal coordination at the His? active site, and the magnitude of this distortion correlates inversely with the CA stability. In a second study, the thermodynamics of the stability provided by two Zn?? ions coordinating to three His residues in the insulin hexamer quaternary structure were quantified and found to be worth 40 kcal/mol of enthalpy and 2kcal/mol of free energy to the stability, which was further enhanced in the presence of allosteric effectors (Ca??,Cl ?, phenol). In a third study, binding of Ni?? or Cu?? to the N-terminus of bovine serum albumin (BSA) did not increase the stability of the protein. However, metal coordination (Cu? ?, Hg??) to the free Cys residue of reduced BSA contributes 8-33 ?C to the T[subscript m] and 10-130 kcal/mol to the unfolding enthalpy. In a fourth study, investigations of iron-Cys ligation in engineered cytochrome c variants revealed redox-dependent stabilization of the ferric state by 3-4 kcal/mol. Increased stability of Fe??-Cys, compared with Fe??-Cys, was found to be driven primarily by entropic factors. Finall, redox-dependent stability and alkaline transitions of these proteins, as well as comparisons to Cys binding studies with a model heme peptide, demonstrated that the dynamics of the protein scaffold plays an important role in stabilizing the iron-Cys coordination in heme proteins.
Description	xvi, 265 leaves : ill. (mostly col.)
Format	application/pdf
College	Dartmouth College. Department of Chemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1271

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