Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 525, Issue 1, Pages 82-91Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2012.05.012
Keywords
Electron transfer; Tyrosyl radical; Oxidation; Nitration; Computer simulation
Categories
Funding
- Howard Hughes Medical Institute
- Agencia Nacional de Investigacion e Innovacion (ANII)/Fondo Clemente Estable [FCE_2486, FCE_362]
- Comiskin Sectorial de Investigacion Cientifica
- National Institutes of Health [2 RO1Hl063119-05]
- [PICT-2010-0416]
- [UBA CyT 2010/2012]
- [PIP 12-200801-01207]
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Experimental studies in hemeproteins and model Tyr/Cys-containing peptides exposed to oxidizing and nitrating species suggest that intramolecular electron transfer (IET) between tyrosyl radicals (Tyr-O-center dot) and Cys residues controls oxidative modification yields. The molecular basis of this IET process is not sufficiently understood with structural atomic detail. Herein, we analyzed using molecular dynamics and quantum mechanics-based computational calculations, mechanistic possibilities for the radical transfer reaction in Tyr/Cys-containing peptides in solution and correlated them with existing experimental data. Our results support that Tyr-O-center dot to Cys radical transfer is mediated by an acid/base equilibrium that involves deprotonation of Cys to form the thiolate, followed by a likely rate-limiting transfer process to yield cysteinyl radical and a Tyr phenolate; proton uptake by Tyr completes the reaction. Both, the pKa values of the Tyr phenol and Cys thiol groups and the energetic and kinetics of the reversible IET are revealed as key physico-chemical factors. The proposed mechanism constitutes a case of sequential, acid/base equilibrium-dependent and solvent-mediated, proton-coupled electron transfer and explains the dependency of oxidative yields in Tyr/Cys peptides as a function of the number of alanine spacers. These findings contribute to explain oxidative modifications in proteins that contain sequence and/or spatially close Tyr-Cys residues. (C) 2012 Elsevier Inc. All rights reserved.
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