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Molecular dynamics of the human RhD and RhAG blood group proteins.

ABSTRACT: Introduction: Blood group antigens of the RH system (formerly known as "Rhesus") play an important role in transfusion medicine because of the severe haemolytic consequences of antibodies to these antigens. No crystal structure is available for RhD proteins with its partner RhAG, and the precise stoichiometry of the trimer complex remains unknown. Methods: To analyse their structural properties, the trimers formed by RhD and/or RhAG subunits were generated by protein modelling and molecular dynamics simulations were performed. Results: No major differences in structural behaviour were found between trimers of different compositions. The conformation of the subunits is relatively constant during molecular dynamics simulations, except for three large disordered loops. Discussion: This work makes it possible to propose a reasonable stoichiometry and demonstrates the potential of studying the structural behaviour of these proteins to investigate the hundreds of genetic variants relevant to transfusion medicine.

SUBMITTER: Floch A

PROVIDER: S-EPMC10985258 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Molecular dynamics of the human RhD and RhAG blood group proteins.

Floch Aline A Galochkina Tatiana T Pirenne France F Tournamille Christophe C de Brevern Alexandre G AG

Frontiers in chemistry 20240319

<b>Introduction:</b> Blood group antigens of the RH system (formerly known as "Rhesus") play an important role in transfusion medicine because of the severe haemolytic consequences of antibodies to these antigens. No crystal structure is available for RhD proteins with its partner RhAG, and the precise stoichiometry of the trimer complex remains unknown. <b>Methods:</b> To analyse their structural properties, the trimers formed by RhD and/or RhAG subunits were generated by protein modelling and ...[more]

PMID: 38566898

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Project description:Cholera is caused by Vibrio cholerae and is an example of a blood-group-dependent disease. Recent studies suggest that the receptor-binding B subunit of the cholera toxin (CT) binds histo-blood group antigens at a secondary binding site. Herein, we studied the conformational dynamics of Lewis Y (LeY) oligosaccharides, H-tetrasaccharides and A-pentasaccharides, in aqueous solution by conducting accelerated molecular dynamics (aMD) simulations. The flexible nature of both oligosaccharides was displayed in aMD simulations. Furthermore, aMD simulations revealed that for both oligosaccharides in the free form, 4C1 and 1C4 puckers were sampled for all but GalNAc monosaccharides, while either the 4C1 (GlcNAc, Gal, GalNAc) or 1C4 (Fuc2, Fuc3) pucker was sampled in the CT-bound forms. In aMD, the complete transition from the 4C1 to 1C4 pucker was sampled for GlcNAc and Gal in both oligosaccharides. Further, we have observed a transition from the open to closed conformer in the case of A-pentasaccharide, while H-tetrasaccharide remains in the open conformation throughout the simulation. Both oligosaccharides adopted an open conformation in the CT binding site. Moreover, we have investigated the molecular basis of recognition of LeY oligosaccharides by the B subunit of the cholera toxin of classical and El Tor biotypes using the molecular mechanics generalized Born surface area (MM/GBSA) scheme. The O blood group determinant, H-tetrasaccharide, exhibits a stronger affinity to both biotypes compared to the A blood group determinant, A-pentasaccharide, which agrees with the experimental data. The difference in binding free energy between O and A blood group determinants mainly arises due to the increased entropic cost and desolvation energy in the case of A-pentasaccharide compared to that of H-tetrasaccharide. Our study also reveals that the terminal Fuc3 contributes most to the binding free energy compared to other carbohydrate residues as it forms multiple hydrogen bonds with CT. Overall, our study might help in designing glycomimetic drugs targeting the cholera toxin.

Dataset Information

Molecular dynamics of the human RhD and RhAG blood group proteins.

Publications

Molecular dynamics of the human RhD and RhAG blood group proteins.

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