Two different views of transport. (A) Original model of phosphate exchange proposed by Peter Mitchell in the 1950s (Mitchell, 1957). The transporter (dark hash marks) alternates between outward- and inward-facing transitions with phosphate being delivered along the vertical transition on the right and the protein resetting along the left vertical transition. The reaction can only occur in a single file manner along this linear, closed pathway. In this drawing, the transporter creates an internal bond with itself (white rectangle) to satisfy the lack of the bound substrate, but the possibility of an effluxed substrate on the resetting step is mentioned in the paper making the model valid as an antiporter. (B) Free-exchange model of EmrE transport proposed by the Henzler-Wildman laboratory. EmrE is suggested to adopt many more states than the exchanger in A, and these states are more highly connected. Hence, there is not just one linear reaction path through this state space, but instead, many reaction cycles exist with different stoichiometries and varying amounts of “leak.” The red circle is a proton, and the green hexagon is a drug molecule. EmrE is denoted by E_ext (external facing) or E_int (internal facing). The symbols E, ED, EHD, EH, and EHH denote EmrE only, drug bound, drug bound with a single proton, and single- and double-bound proton states, respectively.