Lanthanides Gd and Tm Can Inhibit Carnitine/Acylcarnitine Transporter: Insights from All-Atoms Simulations.

Abstract

Recent experimental evidence highlighted the inhibition of carnitine/acylcarnitine carrier (CAC),an important mitochondrial transmembrane protein for living organisms,by the early lanthanide Pr3+.An explanation of such behaviour was found in the preference of the cation for aminoacids like aspartate and glutamate containing a carboxylate in the sidechain,laying in the inter-membrane space.Interaction of the cation with these residues can cause halt the transfer of the protein's substrates between the matrix and cytoplasm thus opening to new scenarios concerning the CAC-metal interactions and its relative inhibition.In the present work,the panel of metals binding the CAC protein is predictively expanded including Gd3+ and Tm3+,selected as representative species of middle and late lanthanides,respectively.A more realistic membrane-containing model of the protein was built and the comparative analysis of the molecular dynamics (MD) simulations of CAC apo-form with its complexed systems,named CAC-Pr,CAC-Gd and CAC-Tm,was performed.The analysis of the trajectories revealed that the inhibition is caused by the coordination of D132 and E179 to the cations and that such interactions generate a reorganization of important salt-bridges inside the framework of CAC.In detail,MD simulations highlighted that a spontaneous conformational change from cytoplasmatic-state (c-state) to matrix-state (m-state) induced by cations and that,in this condition,the protein channel is occluded,thus explaining the inhibition.