ePrints@IIScePrints@IISc Home | About | Browse | Latest Additions | Advanced Search | Contact | Help

Molecular insights of inhibition in sickle hemoglobin polymerization upon glutathionylation: hydrogen/deuterium exchange mass spectrometry and molecular dynamics simulation-based approach

Das, Rajdeep and Mitra, Amrita and Mitra, Gopa and Maity, Dibyajyoti and Bhat, Vijay and Pal, Debnath and Ross, Cecil and Kurpad, Anura V and Mandal, Amit Kumar (2018) Molecular insights of inhibition in sickle hemoglobin polymerization upon glutathionylation: hydrogen/deuterium exchange mass spectrometry and molecular dynamics simulation-based approach. In: BIOCHEMICAL JOURNAL, 475 (13). pp. 2153-2166.

Full text not available from this repository. (Request a copy)
Official URL: http://dx.doi.org/10.1042/BCJ20180306

Abstract

In sickle cell anemia, polymerization of hemoglobin in its deoxy state leads to the formation of insoluble fibers that result in sickling of red blood cells. Stereo-specific binding of isopropyl group of beta Val6, the mutated amino-acid residue of a tetrameric sickle hemoglobin molecule (HbS), with hydrophobic groove of another HbS tetramer initiates the polymerization. Glutathionylation of beta Cys93 in HbS was reported to inhibit the polymerization. However, the mechanism of inhibition in polymerization is unknown to date. In our study, the molecular insights of inhibition in polymerization were investigated by monitoring the conformational dynamics in solution phase using hydrogen/deuterium exchange-based mass spectrometry. The conformational rigidity imparted due to glutathionylation of HbS results in solvent shielding of beta Val6 and perturbation in the conformation of hydrophobic groove of HbS. Additionally, molecular dynamics simulation trajectory showed that the stereo-specific localization of glutathione moiety in the hydrophobic groove across the globin subunit interface of tetrameric HbS might contribute to inhibition in polymerization. These conformational insights in the inhibition of HbS polymerization upon glutathionylation might be translated in the molecularly targeted therapeutic approaches for sickle cell anemia.

Item Type: Journal Article
Additional Information: Copy right for this article belong to PORTLAND PRESS LTD, CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND
Department/Centre: Division of Interdisciplinary Research > Supercomputer Education & Research Centre
Division of Physical & Mathematical Sciences > Mathematics
Depositing User: Id for Latest eprints
Date Deposited: 30 Aug 2018 15:41
Last Modified: 30 Aug 2018 15:41
URI: http://eprints.iisc.ac.in/id/eprint/60533

Actions (login required)

View Item View Item