Differential Stabilities of Mefloquine-Bound Human and Plasmodium falciparum Acyl-CoA-Binding Proteins

[Image: see text] Toxic effects of pharmacological drugs restrict their robust application against human diseases. Although used as a drug in the combinatorial therapy to treat malaria, the use of mefloquine is not highly recommended because of its adverse effects in humans. Mefloquine inhibits the binding of acyl-CoAs to acyl-CoA-binding proteins of Plasmodium falciparum (PfACBPs) and human (hACBP). In this study, we have used molecular dynamics simulation and other computational approaches to investigate the differences of stabilities of mefloquine–PfACBP749 and mefloquine–hACBP complexes. The stability of mefloquine in the binding cavity of PfACBP749 is less than its stability in the binding pocket of hACBP. Although the essential tyrosine residues (tyrosine-30 and tyrosine-33 of PfACBP749 and tyrosine-29 and tyrosine-32 of hACBP) mediate the initial binding of mefloquine to the proteins by π-stacking interactions, additional temporally longer interactions between mefloquine and aspartate-22 and methionine-25 of hACBP result in stronger binding of mefloquine to hACBP. The higher fluctuation of mefloquine-binding residues of PfACBP749 contributes to the instability of mefloquine in the binding cavity of the protein. On the contrary, in the mefloquine-bound state, the stability of hACBP protein is less than the stability of PfACBP749. The helix-to-coil transition of the N-terminal hydrophobic region of hACBP has a destabilizing effect upon the protein’s structure. This causes the induction of aggregation properties in the hACBP in the mefloquine-bound state. Taken together, we describe the mechanistic features that affect the differential dynamic stabilities of mefloquine-bound PfACBP749 and hACBP proteins.