A computational study of structural analysis of Class I human glucose-6-phosphate dehydrogenase (G6PD) variants: Elaborating the correlation to chronic non-spherocytic hemolytic anemia (CNSHA)

Area of Science:

• Biochemistry and Molecular Biology
• Computational Biology and Bioinformatics
• Genetics and Genomics

Background:

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most prevalent human enzyme defect, affecting over 500 million people globally.
• Class I G6PD variants are associated with chronic non-spherocytic hemolytic anemia (CNSHA), a severe form of the condition.
• Current therapeutic options for G6PD deficiency remain limited, necessitating novel treatment strategies.

Purpose of the Study:

• To computationally investigate the structural defects in selected Class I G6PD variants (G6PD^Nashville, G6PD^Alhambra, G6PD^Durham).
• To assess the potential of the AG1 molecule in correcting these structural defects and re-stabilizing the enzyme.
• To elucidate the molecular mechanisms underlying G6PD variants' impact on enzyme function and CNSHA severity.

Main Methods:

• Docking simulations of the AG1 molecule to G6PD variants at the dimer interface and NADP⁺ binding site.
• Molecular dynamics simulations (MDS) to analyze enzyme conformational changes before and after AG1 binding.
• Analysis of structural parameters including RMSD, RMSF, hydrogen bonds, salt bridges, Rg, SASA, and PCA to evaluate CNSHA severity.

Main Results:

• Selected G6PD variants (G6PD^Nashville, G6PD^Durham) lost direct contact with NADP⁺, and key salt bridges were disrupted in all studied variants.
• The AG1 molecule successfully re-stabilized the G6PD enzyme structure by restoring critical interactions.
• Bioinformatics and MDS analyses provided detailed molecular insights into variant-induced functional impairments.

Conclusions:

• The AG1 molecule demonstrates potential as a novel therapeutic agent by promoting activation and structural stabilization in various G6PD variants.
• This study highlights the utility of computational approaches in understanding enzyme defects and guiding drug discovery for G6PD deficiency.
• Restoring enzyme structure and function through molecules like AG1 offers a promising avenue for managing G6PD deficiency-related anemias.