Reassessment of models of facilitated transport and cotransport.

Most membrane transport models are determinate, requiring the transported ligand(s) to bind initially to a vacant site, which undergoes translation and releases ligand to the alternate side. The carrier reverts to its initial position to complete the net transport cycle. Ligand affinity may change during translation, but this must be compensated by an equivalent energy change(s) within the transport cycle. However, any asymmetric cyclic equilibrium deduced on this basis is thermodynamically fallacious. Determinate cotransport models imply lossless stoichiometric relationships between the complexed cotransported ligands. Independent ligand leakage apart from the mobile cotransport complex must occur outside the canonical cotransport pathway. In contrast, stochastic transport models assume independent ligand diffusion through a variably occluded channel(s) containing binding sites where ligands may undergo bimolecular exchanges. Energy dissipation is intrinsic to all stochastic transport models and occurs within the primary transport pathway. Frictional interactions within a shared path generate flow coupling between ligands. The primary driving forces causing transmembrane ligand flows are their electrochemical potential differences between the external solutions. Demonstrations that ligand exchanges in CLC and neurotransmitter transporters can be multimodal, encompassing both "channel"-like high and "transporter"-like lower conductance states and have independently regulated import and export exchange fluxes are major challenges to determinate models but are explicable by transient widening of a close-encounter region within the channel, leading to decreased coupling and enhanced efflux.