Remarkable Similarity in Plasmodium falciparum and Plasmodium vivax Geranylgeranyl Diphosphate Synthase (GGPPS) Dynamics and its Implication for Anti-Malarial Drug Design

Abstract

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 (PfGGPPS) has not been determined, due to difficulties in crystallization. Here, we created a PfGGPPS model using the homologous P.vivax GGPPS X-ray structure as a template. We simulated the modeled PfGGPPS as well as PvGGPPS 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 PfGGPPS and PvGGPPS into closed conformations and via similar mechanisms. Shape-based analysis of the binding sites throughout the simulations suggest that the two enzymes will be readily targeted by the same inhibitors. Finally, we produced three MD-validated conformations of PfGGPPS to be used in future virtual screenings for potential new anti-malarial drugs acting on both PvGGPPS and PfGGPPS.

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We create the first atomistic model for Plasmodium falciparum (Pf)GGPPS, a malaria drug target, based on the homologous Plasmodium vivax protein (PvGGPPS). Extensive conventional and Gaussian accelerated molecular dynamics simulations reveal a striking similarity between the dynamics of the two enzymes, with loop 9-10 controlling the access to the active site and the product, GGPP, preventing the enzyme to adopt fully open conformations. A shape-based analysis of the binding pocket throughout the simulations suggests that the two enzymes will be easily targeted by the same inhibitors and provides three clusters of relevant conformations to be used in future virtual screenings for potential anti-malarial drugs acting on both Pv and PfGGPPS

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