The dynamics of hemoglobin-haptoglobin complexes. Relevance for oxidative stress

Abstract

Haptoglobin (Hp) is a protein with role in oxidative stress prevention, which it fulfills by trapping hemoglobin (Hb) dimers in a strongly-bound complex, thus reducing Hb's ability to engage in oxidative stress reactions which are greatly enhanced when the Hb tetramer falls apart into dimers. A first molecular dynamics (MD) analysis is presented here for the Hb-Hp pair. Also, for the first time the tyrosyl (Tyr) radicals in globins are examined with MD calculations directed at comparing with electron paramagnetic resonance (EPR)-detected parameters, with the aim of identifying the location of free radicals on the globin. Such assignments are needed in order to complete our understanding of the manner in which globins deal with oxidative stress, as well as for the ways the organism deals with the oxidative stress occasionally accidentally amplified by the globins via their reactive heme and Tyr moieties. The EPR-detected free radical in Hb and in Hb:Hp is characterized experimentally by a measurable increase in hydrophobicity upon Hb:Hp complexation and by a constant ∼53° θ angle. The x-ray structure and MD-derived hydrophobicity-related parameters appear to support Y145, Y35 and Y24 as likely locations of the Hb radical – arguing strongly against Y42, Y130 and Y140. The θ values appear to favor Y42, with the MD data nevertheless also arguing in favor of Y35 and, to a lesser extent, Y145 and Y140. Y130 and Y24 appear the least likely candidates according to the θ values, especially in view of the MD data. Overall, Y35 and Y145 appear to be the two candidates with least arguments against them for satisfying the two criteria (θ values and hydrophobicity) for matching the experimentally-observed EPR radical in Hb and Hb:Hp.