The multidrug resistance transporter NorM is an important drug resistance pump and plays a critical role in multidrug resistance in bacteria and mammals. In this study we carried out molecular dynamics simulation to study the mechanism of Na+ binding and dynamical structures of two long loops in the substrate-releasing process in substrate binding NorM. Our simulation study identified several key residues (D41, E261 D377) along the Na+ binding pathway and a multi-state ion-binding mechanism is proposed based on the simulation study. In this proposed model, the transport of Na+ is a multi-stage process with D41 being the first station for binding to Na+, followed by Na+ binding to the second station E262 and finally to the cation-binding site of E262 and D377. During the transport of Na+, the transmembrane components TM1, TM7 and TM2 are rearranged to facilitate the ion transport as well conformational changes of NorM to a closed state. Further, substrate-bound simulation revealed that Loop3-4 and Loop9-10 control the substrate-releasing process.

ECF (energy-coupling factor) transporters are responsible for many micronutrients uptake in organisms. The recently reported S-component structure of the ECF transporter FolT provides a solid basis to study the mechanism of the substrate folate binding. In this work, several kinds of molecular dynamics (MD) simulations methods are applied to investigate the dynamics of loops in folate-bound and folate-free state of FolT. Our study found: (1) The loops of the S-component play important roles and cooperate with each other in ligand binding process (namely, loop1, loop3 and loop5); (2) Although loop3 and loop5 are quite important in folate binding, our study showed that Loop1 is the dominant factor and serves as the gate controlling the folate binding and (3) The Steered molecular dynamics simulation shows evidence for a toppling working model proposed previously for the releasing process of the substrate folate.