Abstract
Major facilitator superfamily (MFS) of transporters consist of three subclasses: symporters, uniporters, and antiporters. We have performed a variety of equilibrium and non-equilibrium all-atom molecular dynamics (MD) simulations on bacterial proton-coupled oligopeptide transporter GkPOT, glucose transporter 1 (GluT1), and glycerol-3-phosphate transporter (GlpT) to compare the similarities and differences of the conformational dynamics of three different classes of the MFS superfamily in an explicit membrane environment. Our results of GkPOT reveal, with the aid of non-equilibrium pulling simulations and string method with swarms of trajectories, that the transition from the inward-facing (IF) to the outward-facing (OF) conformation whilst leaving the key inter-bundle salt-bridge of E310-R43 intact. Admittedly in comparison to previous GlpT simulations, the key salt-bridge must break to allow for the conformation to be explored. In spite of this, GluT1, transitions from the IF to the OF state spontaneously and then transitions to an OF-occluded conformation. All simulations are performed in the apo state of protein and reveal that despite their similarities, they use very different mechanisms to transition between the IF and OF states and they do so on very different timescales.