A computational study of structural differences of binding of NADP and G6P substrates to G6PD Mediterranean, G6PD A-, G6PD Cairo and G6PD Gaza mutations.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X-linked inherited enzymopathic disorder that may lead to transfusion-requiring acute hemolytic anemia (AHA) triggered by fava beans ingestion, infection or some drugs. The gene encoding for G6PD carries a large number of genetic variants that have varying pathogenicity. We reported on three G6PD variants in the Gaza Strip Palestinian population with differing clinical impacts and frequencies: G6PD Mediterranean, African G6PD A-, and G6PD Cairo. We also identified a novel G6PD missense (Ser179Asn) mutation c.536G > A "G6PD Gaza". In this work we explore the effect of these four genetic variants on the structural and substrate (NADP and G6P) binding characteristics of the G6PD enzyme using the Monte Carlo (MC) flexible docking and molecular dynamics (MD) simulation approaches. We report that G6PD A-, G6PD Mediterranean, G6PD Cairo and G6PD Gaza mutations cause significant structural changes in G6PD enzyme to induce conformational instability leading to the loss of binding of one or both substrates and are causative of G6PD deficiency.