Remarkable similarity in Plasmodium falciparumPlasmodium falciparum and Plasmodium vivaxPlasmodium vivax geranylgeranyl diphosphate synthase dynamics and its implication for antimalarial drug design

摘要

> Malaria, mainly caused by Plasmodium falciparum and Plasmodium vivax, has been a growing cause of morbidity and mortality. P.?falciparum is more lethal than is P.?vivax , but there is a vital need for effective drugs against both species. Geranylgeranyl diphosphate synthase ( GGPPS ) is an enzyme involved in the biosynthesis of quinones and in protein prenylation and has been proposed to be a malaria drug target. However, the structure of P.?falciparum GGPPS ( Pf GGPPS ) has not been determined, due to difficulties in crystallization. Here, we created a Pf GGPPS model using the homologous P.vivax GGPPS X‐ray structure as a template. We simulated the modeled Pf GGPPS as well as Pv GGPPS using conventional and Gaussian accelerated molecular dynamics in both apo‐ and GGPP ‐bound states. The MD simulations revealed a striking similarity in the dynamics of both enzymes with loop 9‐10 controlling access to the active site. We also found that GGPP stabilizes Pf GGPPS and Pv GGPPS into closed conformations and via similar mechanisms. Shape‐based analysis of the binding sites throughout the simulations suggests that the two enzymes will be readily targeted by the same inhibitors. Finally, we produced three MD ‐validated conformations of Pf