Thermodynamics of ABC transporters

Abstract

ABC transporters form the largest of all transporter families, and their structural study has made tremendous progress over recent years. However, despite such advances, the precise mechanisms that determine the energy-coupling between ATP hydrolysis and the conformational changes following substrate binding remain to be elucidated. Here, we present our thermodynamic analysis for both ABC importers and exporters, and introduce the two new concepts of differential-binding energy and elastic conformational energy into the discussion. We hope that the structural analysis of ABC transporters will henceforth take thermodynamic aspects of transport mechanisms into account as well.

Keywords: ABC transporters; differential-binding energy; elastic conformational energy; energy-coupling.

Figure 1

Schematic diagrams of functional cycles of ABC transporters. (A) Simplified ABC importer. (B) Type-I SBP-dependent importer. (C) Type-II SBP-dependent importer. In both panels (B) and (C), the cyan arrow indicates the direction of the electrostatic force applied by the membrane potential on the SBP-importer complex. This force may facilitate the formation of the ATPase active site. (D) ABC exporter. For a simple ABC exporter, the transition from the second/middle to the third/right conformation is powered by ΔG_E. ATP hydrolysis drives the resetting of the transporter back to its resting state, C_In. For a P-gp like exporter, the second/middle conformation is in equilibrium with the third/right one. ATP hydrolysis drives both substrate release and conformational resetting. For all panels, the first/left conformation is presumably the resting state. PDB access codes of representative crystal structures are listed at the bottom

Figure 2

Schematic free-energy landscape of ABC transporters. (A) Simplified importer (See Fig. 1A). (B) Type I importer, maltose transporter complex of E. coli (MalFGK₂-E) (See Fig. 1B and Ref. (Austermuhle et al., 2004)). (C) Type-II importer (See Fig. 1C). (D) Simplified exporter (See Fig. 1D). (E) P-gp like exporter (See Ref. (Sauna and Ambudkar, 2000)). A free-energy landscape plot describes the thermodynamic relationship between different states, without attention to kinetic issues. Horizontal lines represent states, with imaginary states in dashed lines. Tilted lines represent transitions between states (note that detailed transition-state barriers are not taken into consideration). Components in red are related to the substrate transport, those in green to ATP hydrolysis. Subscripts L, R, D, and E stand for energy terms associated with loading, releasing, differential binding, and elastics, respectively. Because the transport process is cyclical, the choice of the starting point is, in principle, arbitrary. Therefore, the starting and ending states are identical, only differing in the release of heat (Q) during one transport cycle. Thus, the end state must be below the starting state. Locally, any transition of positive ΔG must be driven by a neighboring transition of a negative ΔG. In such cases, neighboring events may be either sequentially ordered or simply clustered. For a sequential order, one event may lower the transition energy barrier of the next event, thus making the kinetics of the latter feasible. Clustered events, in contrast, occur simultaneously. Dividing such a clustered event into separate energy terms is mostly conceptual (see Appendix for further details). Note that for simplicity, release of P_i, a product of ATP hydrolysis, is not shown. Instead, it is absorbed in the ADP terms. Nevertheless, it is entirely possible that P_i and ADP dissociate from the transporter at separate steps of the process