Molecular dynamics of G6PD variants from sub-Saharan Africa

Jorge Batista da Rocha; Houcemeddine Othman; Scott Hazelhurst

doi:10.1016/j.bbrep.2022.101236

Molecular dynamics of G6PD variants from sub-Saharan Africa

Biochem Biophys Rep. 2022 Mar 17:30:101236. doi: 10.1016/j.bbrep.2022.101236. eCollection 2022 Jul.

Authors

Jorge Batista da Rocha^{1

2}, Houcemeddine Othman¹, Scott Hazelhurst^{1

3}

Affiliations

¹ Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
² Division of Human Genetics, National Health Laboratory Service, and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
³ School of Electrical and Information Engineering, University of the Witwatersrand, Johannesburg, South Africa.

Abstract

Precision medicine uses genomic guidance to improve drug treatment safety and efficacy. Prior knowledge of genetic variant impact can enable such strategies, but current knowledge of African variants remains scarce. G6PD variants are linked to haemolytic adverse effects for a number of drugs commonly used in African populations. We have investigated a set of G6PD variants with structural bioinformatics techniques to further characterise variants with known effect, and gain insights into variants with unknown impact. We observed wide variations in patterns of root-mean-square deviation between wild-type and variant structures. Variants with known, highly deleterious impact show structural effects which may likely result in the destabilisation of the G6PD homodimer. The V68M and N126D variants (which are both common across African populations, and together form the A- haplotype) induce large conformational shifts in the catalytic NADP+ binding domain. We observed a greater impact for the haplotype than for each of the individual variants in these cases. A novel African variant (M207T) shows the potential to disrupt interactions within the protein core, urging further investigation. We explore how characterising the molecular impact of African G6PD variants can enable advanced strategies for precision medicine, as well as impact the use of novel therapeutics aiming to treat G6PD deficiency. This knowledge can assist in bridging current knowledge gaps, and aid to facilitate precision medicine applications in African populations.

Keywords: Africa; G6PD; Molecular Dynamics; Precision medicine; Structural bioinformatics; Variants.