Molecular Dynamics Simulaon of the Fo Domain of Trypanosoma brucei FoF1-ATP Synthase to Uncover Water Channel Pathways

Abstract

Trypanosoma brucei is a unicellular parasite responsible for causing human African trypanosomiasis (HAT). The unique life cycle of the parasite, infecting tsetse flies and humans, is supported by its reversible FoF1-ATP synthase. The study aims to characterize the water channel pathways within the Fo domain of T. brucei FoF1-ATP synthase to elucidate its proton translocation mechanism. The Fo domain was inserted into POPC and DOPC membrane systems, with each membrane system being replicated three times. Equilibration and production simulation for each replicate was performed for 20 ns and 100 ns, respectively. The lumenal and cytoplasmic half-channels were solvated in all replicates during the simulation, solvating the key-glutamate E102. A DOPC was shown to insulate the lumenal half-channel, replacing the role of the absent bH2. The lumenal half-channel was solvable through the rear entry, involving structurally determined key residues H75, H19, D202, and H155, as well as manually identified residues Y74, N150, and Y199. The cytoplasmic half-channel had a more open configuration, solvating key residues D223, R139, and R146, as well as manually identified residues E132, RQ219, S135, S142, and T143. The key-arginine was crucial in separating both half-channels; its rotamer is supported by coordinating water molecules with Q209. Phylogenetic analysis of subunit-a revealed that T. brucei is evolutionarily divergent from other species.