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Please use this identifier to cite or link to this item: http://hdl.handle.net/10451/5783

Title: Application of QM and MM methodologies to cytochrome c3: charge parametrization of the heme group for classic force fields
Authors: Henriques, João Manuel Almeida
Advisor: Machuqueiro, Miguel Ângelo dos Santos
Keywords: Cytochrome c3
Heme group
Charge parameterization
Redox titration
Constant-(pH,E) MD
Teses de mestrado - 2010
Issue Date: 2010
Abstract: In 2009, Machuqueiro and Baptista used Desulfovibrio vulgaris Hildenborough type I cytochrome c3 in the validation of their new implementation of the stochastic titration method, the constant-(pH,E) MD method. DvH-TpI-c3 is a small globular and monomeric tetraheme protein present in the periplasm of the sulfate reducing bacteria DvH. It is constituted by 107 residues plus four hemes covalently bound to cysteines in the polypeptide chain together with bis-histidinyl axial ligation. Therefore, it constitutes a tight densely packed structure where the heme reduction potentials are very close, making it a very demanding test case in terms of prediction. When tested, this method was shown to yield better results when a high dielectric constant, ", was assigned to the protein region. This dependence on " was never found in previous constant-pH MD simulations and poor heme charge parameterization may have been responsible for this effect. Hence, the main goal of this work was to refine the QM parameterization of the redox centers, i.e. obtain new and more accurate charge sets, incorporate them in the new 53A6 GROMOS force field, and finally run constant-(pH,E) MD simulations with a " of 2. Single and multi-conformational approaches were tested using the RESP scheme. Merz-Kollman and CHELPG methods were also used. All tested charge sets and respective charge parameterization methods were found to be valid, and there is not enough margin to unequivocally select one method as the absolute best. Still, the RESP fitting procedure is much more versatile than CHELPG and Merz-Kollman, making it a better suited tool for a generalized derivation of partial atomic charges. When applied to the constant-(pH,E) MD method, these new and more accurate charge sets, enabled us to improve Machuqueiro and Baptista's results. We were, however, unsuccessful in fully reproducing all experimental data. Theoretical and experimental results systematically disagreed when predicting the Ehalf values for hemes III and IV. The reason behind this incongruity is something we plan to investigate in future work.
Description: Tese de mestrado, Bioquímica, Universidade de Lisboa, Faculdade de Ciências, 2010
URI: http://hdl.handle.net/10451/5783
Appears in Collections:FC - Dissertações de Mestrado

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