Molecular dynamics simulation of closed and open state models of magnesium transporter in lipid bilaye

Abstract

Magnesium ion (Mg2+) plays a crucial role for biological processes such as DNA and protein synthesis, oxidative phosphorylation reaction and enzyme metabolism. Despite its biological abundance and importance, little is known about the transport mechanism of Mg2+ CorA is the primary Mg2+ transport protein in prokaryotic organisms. The crystal structures of CorA from Thermogota Maritima were determined in the presence of Mg2+, corresponding to a closed state. However, the open state conformation has remained uncharacterized, thus limiting our understanding of the functional mechanism of Mg2+ transport in biological system. In this study, an open conformation has been constructed using electron paramagnetic resonance data and PaDSAR approach. Subsequently, molecular dynamics (MD) simulations of the closed and open conformations in lipid bilayer have been performed to understand the relation between structure and function of the protein. A structure model of the open conformation showed the stalk helices being closer to the symmetry axis while the TM1 helices move further away from the principal axis. Such structural arrangement has led to an increase of the pore cavity in the membrane region. From the MD results, all structural domains of the open conformation are more dynamics than those of the closed state. Within the protein, the cytoplasmic domain and the periplasmic loop are highly flexible with respect to the stalk and transmembrane helices. An analysis of Mg2+ coordination of all binding sites in the simulations of the closed conformation revealed hexa-coordinated Mg2+ with ligands mostly from either aspartate residues and/or water. The force profiles obtained from a steered molecular dynamics method showed a high driving force for the movement of Mg2+ at the periplasmic entrance of the pore in both closed and open states, suggesting a possible role of the periplasmic loop for the ion-selective property. The present study provided more understanding for the transport mechanism in the primary Mg2+ transport system.