Dixit, VA;
Blumberger, J;
Vyas, SK;
(2021)
Methemoglobin formation in mutant hemoglobin α chains: electron transfer parameters and rates.
Biophysical Journal
, 120
(17)
pp. 3807-3819.
10.1016/j.bpj.2021.07.007.
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Abstract
Hemoglobin-mediated transport of dioxygen (O2) critically depends on the stability of the reduced (Fe2+) form of the heme cofactors. Some protein mutations stabilize the oxidized (Fe3+) state (methemoglobin, Hb M), causing methemoglobinemia, and can be lethal above 30%. The majority of the analyses of factors influencing Hb oxidation are retrospective and give insights only for inner-sphere mutations of heme (His58, His87). Herein, we report the first all-atom molecular dynamics simulations on both redox states and calculations of the Marcus electron transfer (ET) parameters for the α chain Hb oxidation and reduction rates for Hb M. The Hb wild-type (WT) and most of the studied α chain variants maintain globin structure except the Hb M Iwate (H87Y). The mutants forming Hb M tend to have lower redox potentials and thus stabilize the oxidized (Fe3+) state (in particular, the Hb Miyagi variant with K61E mutation). Solvent reorganization (λsolv 73–96%) makes major contributions to reorganization free energy, whereas protein reorganization (λprot) accounts for 27–30% except for the Miyagi and J-Buda variants (λprot ∼4%). Analysis of heme-solvent H-bonding interactions among variants provide insights into the role of Lys61 residue in stabilizing the Fe2+ state. Semiclassical Marcus ET theory-based calculations predict experimental kET for the Cyt b5-Hb complex and provide insights into relative reduction rates for Hb M in Hb variants. Thus, our methodology provides a rationale for the effect of mutations on the structure, stability, and Hb oxidation reduction rates and has potential for identification of mutations that result in methemoglobinemia.
| Type: | Article |
|---|---|
| Title: | Methemoglobin formation in mutant hemoglobin α chains: electron transfer parameters and rates |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.bpj.2021.07.007 |
| Publisher version: | https://doi.org/10.1016/j.bpj.2021.07.007 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Physics and Astronomy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10135092 |
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