Molecular basis of intramolecular electron transfer in proteins during radical-mediated oxidations: computer simulation studies in model tyrosine-cysteine peptides in solution. Arch Biochem Biophys 2012 Sep 01;525(1):82-91
Date
05/30/2012Pubmed ID
22640642Pubmed Central ID
PMC3414218DOI
10.1016/j.abb.2012.05.012Scopus ID
2-s2.0-84864288909 (requires institutional sign-in at Scopus site) 30 CitationsAbstract
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(·)) 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(·) 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.
Author List
Petruk AA, Bartesaghi S, Trujillo M, Estrin DA, Murgida D, Kalyanaraman B, Marti MA, Radi RAuthor
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Computer SimulationCysteine
Electron Transport
Free Radicals
Kinetics
Molecular Dynamics Simulation
Peptides
Proteins
Quantum Theory
Solutions
Tyrosine
Water
