Research Article: Functional and Structural Insights Revealed by Molecular Dynamics Simulations of an Essential RNA Editing Ligase in Trypanosoma brucei

Date Published: November 14, 2007

Publisher: Public Library of Science

Author(s): Rommie E. Amaro, Robert V. Swift, J. Andrew McCammon, Jennifer Keiser

Abstract: RNA editing ligase 1 (TbREL1) is required for the survival of both the insect and bloodstream forms of Trypanosoma brucei, the parasite responsible for the devastating tropical disease African sleeping sickness. The type of RNA editing that TbREL1 is involved in is unique to the trypanosomes, and no close human homolog is known to exist. In addition, the high-resolution crystal structure revealed several unique features of the active site, making this enzyme a promising target for structure-based drug design. In this work, two 20 ns atomistic molecular dynamics (MD) simulations are employed to investigate the dynamics of TbREL1, both with and without the ATP substrate present. The flexibility of the active site, dynamics of conserved residues and crystallized water molecules, and the interactions between TbREL1 and the ATP substrate are investigated and discussed in the context of TbREL1’s function. Differences in local and global motion upon ATP binding suggest that two peripheral loops, unique to the trypanosomes, may be involved in interdomain signaling events. Notably, a significant structural rearrangement of the enzyme’s active site occurs during the apo simulations, opening an additional cavity adjacent to the ATP binding site that could be exploited in the development of effective inhibitors directed against this protozoan parasite. Finally, ensemble averaged electrostatics calculations over the MD simulations reveal a novel putative RNA binding site, a discovery that has previously eluded scientists. Ultimately, we use the insights gained through the MD simulations to make several predictions and recommendations, which we anticipate will help direct future experimental studies and structure-based drug discovery efforts against this vital enzyme.

Partial Text: The existence and widespread occurrence of several devastating trypanosomal tropical diseases, such as Chagas’ disease and African sleeping sickness, cause an estimated 1 million deaths each year in developing countries [1]. In 2005, the completely sequenced genomes of Trypanosoma brucei, the causative agent of African sleeping sickness, T. cruzi, the causative agent of Chagas disease, and Leishmania major, the causative agent of Leishmaniasis, were published, yet, despite these great genomic successes, the need for effective and suitable drugs still remains [2]. Currently available drugs were developed in the first half of the twentieth century and they are toxic, difficult to deliver and often ineffective [3].



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