Ion-Induced Dipole Interactions Matter in Metadynamics Simulation of Transition Metal Ion Transporters

Metal transporters play crucial roles in the homeostasis and detoxification of beneficial and toxic metals in the human body. Due to experimental limitations in studying some metal transporters, numerous simulation studies have been conducted to understand the mechanisms of metal transport. However, studying the transport of divalent metal ions across the plasma membrane by metal transporters has been challenging with traditional molecular dynamics (MD) simulations. The metal ions often become trapped inside the transporter due to encountering high energy barriers during the transport process. In this study, we combined a recently developed metadynamics setup, known as well-tempered (WT) volume-based MTD, with the 12-6-4 Lennard-Jones (LJ) model representing transition metal-His/Asp/Glu side chain interactions. We used this approach to investigate the mechanism of action of a Zrt-/Irt-like protein (ZIP) transporter and compared the results with simulations using standard 12-6 LJ parameters for the transition metal-His/Asp/Glu side chain interactions. Our results show that the 12-6-4 LJ model for transition metal-His/Asp/Glu side chain interactions samples conformational space more broadly than the standard 12-6 LJ model for the same interactions in MTD simulations, facilitating the sampling of states that are hard to reach with the standard 12-6 model within the same time scale. This is even more remarkable given the fact that the model is dominated by 12-6 LJ interactions for the majority of the system, while the transition metal-His/Asp/Glu side chain interactions are the only interactions using the 12-6-4 LJ model. Hence, a small subset of interactions significantly modifies the states sampled by the entire protein leading to a more frequent observation of the transport of the transition metal ion. Overall, using 12-6-4 LJ to model the transition metal-His/Asp/Glu side chain interactions increases the potential for discovering additional metastable states by enabling metal ions to traverse more freely along the defined transport pathways.