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

Recent experimental evidence highlighted the inhibition of carnitine/acylcarnitine carrier (CAC), an important mitochondrial transmembrane protein for living organisms, by the early lanthanide Pr³⁺. A possible explanation of such a behaviour was found in the preference of the cation for amino acids like aspartate and glutamate containing a carboxylate in the side chain, 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.