On the Binding Free Energy and Molecular Origin of Sickle Cell Hemoglobin Aggregation

Galamba, N.; Pipolo, Silvio

Type de document :

Article dans une revue scientifique

DOI :

10.1021/acs.jpcb.8b03708

URL permanente :

http://hdl.handle.net/20.500.12210/12951

Titre :

On the Binding Free Energy and Molecular Origin of Sickle Cell Hemoglobin Aggregation

Auteur(s) :

Galamba, N. [Auteur]

Pipolo, Silvio [Auteur]

Unité de Catalyse et Chimie du Solide - UMR 8181 [UCCS]

Titre de la revue :

The Journal of Physical Chemistry B

Nom court de la revue :

J. Phys. Chem. B

Numéro :

122

Pagination :

7475-7483

Éditeur :

ACS

Date de publication :

2018-08-02

Mot(s)-clé(s) en anglais :

Electrostatics
Peptides and proteins
Monomers
Aggregation
Potential energy

Discipline(s) HAL :

Chimie/Chimie théorique et/ou physique

Résumé en anglais : [en]

Protein aggregation is associated with various diseases, including Alzheimer and Parkinson as well as sickle cell disease (SCD). From a molecular point of view, protein aggregation depends on a complex balance of electrostatic ...
Lire la suite >Protein aggregation is associated with various diseases, including Alzheimer and Parkinson as well as sickle cell disease (SCD). From a molecular point of view, protein aggregation depends on a complex balance of electrostatic and hydrophobic interactions mediated by water. An impressive manifestation of the importance of this balance concerns the human hemoglobin (HbA) mutant, HbS (sickle cell Hb), where a single substitution at the 6th position of HbA β-chains, from glutamic acid to valine, causes the polymerization of deoxygenated HbS (deoxy-HbS), responsible for SCD. HbS polymerization is believed to occur via a double nucleation mechanism initiated by the formation of HbS fibers (homogeneous nucleation), followed by fiber growth. Furthermore, it was proposed that homogeneous nucleation proceeds through a two-step mechanism, where metastable dense clusters play the role of nucleation precursors. Thus, hindering or delaying the formation of such precursors could represent a potential SCD therapeutic route. Here, we study, through molecular dynamics, the binding free energy and protein–protein contacts involved in the deoxy-HbS dimer aggregation and stabilization process. A binding free energy of ∼−14.0 ± 1 kcal/mol is estimated from a one-dimensional potential of mean force. Analysis of protein–protein interactions shows that both electrostatic and van der Waals interactions play an important role on the aggregation of HbS. With respect to the former, our results indicate that aggregation is largely favored by the formation of salt bridges (SB), mostly, Lys–Glu, Lys–Asp, and Heme-Lys SB, which outweigh electrostatic repulsions involving similar residues. Thus, our results suggest that a potential antisickling drug could be one with the ability to weaken or hinder the formation of a few SB between carboxylate and ammonium groups.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

ENSCL
CNRS
Centrale Lille
Univ. Artois
Université de Lille

Collections :

Unité de Catalyse et Chimie du Solide (UCCS) - UMR 8181

Équipe(s) de recherche :

Modélisation et spectroscopies (MODSPEC)

Date de dépôt :

2019-09-25T15:07:00Z
2021-03-18T12:58:59Z

Numéro de version	Lien	Date de modification
2	20.500.12210/12951*	2021-03-18T12:47:20Z
1	20.500.12210/12951.1	2019-09-25T15:07:00Z

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