Theoretical study of active secondary transport: Unexpected differences in molecular mechanisms for antiporters and symporters

Abstract

Successful functioning of biological cells relies on efficient translocation of different materials across cellular membranes. An important part of this transportation system is membrane channels that are known as antiporters and symporters. They exploit the energy stored as a trans-membrane gradient of one type of molecules to transport the other types of molecules against their gradients. For symporters, the directions of both fluxes for driving and driven species coincide, while for antiporters, the fluxes move in opposite directions. There are surprising experimental observations that despite differing only by the direction of transport fluxes, the molecular mechanisms of translocation adopted by antiporters and symporters seem to be drastically different. We present chemical-kinetic models to quantitatively investigate this phenomenon. Our theoretical approach allows us to explain why antiporters mostly utilize a single-site transportation when only one molecule of any type might be associated with the channel. At the same time, the transport in symporters requires two molecules of different types to be simultaneously associated with the channel. In addition, we investigate the kinetic constraints and efficiency of symporters and compare them with the same properties of antiporters. Our theoretical analysis clarifies some important physical–chemical features of cellular trans-membrane transport.

Understanding Mechanisms of Secondary Active Transport by Analyzing the Effects of Mutations and Stoichiometry

“…Here, the dimensionless parameter x specifies a catalytic effect of modifying the conformational transition rates after the molecular associations of molecules A or B to the channel. 20,21 The important advantage of chemical-kinetic model is that all dynamic properties of antiporters can be explicitly evaluated in terms of individual transition rates. 20,21 For example, the stationary flux of driven particles B can be written as…”

“…20,21 The important advantage of chemical-kinetic model is that all dynamic properties of antiporters can be explicitly evaluated in terms of individual transition rates. 20,21 For example, the stationary flux of driven particles B can be written as…”

“…The processes associated with secondary active transport in biological cells have been intensively investigated by using a wide spectrum of experimental and theoretical approaches. ,− It is now well established, both structurally and kinetically, that the molecular transport via antiporters and symporters is taking place via a sequence of conformational transitions that alternate the exposure of the channels to different sides of the cellular membrane. ,, However, many aspects of the mechanisms of the secondary active transport still remain not well understood. For example, it is still unclear how specific mutations in membrane channels, which is one of the main experimental methods of probing their mechanisms, affect the translocation dynamics and efficiency. , This is because the analysis of experimentally measured dynamic properties utilizes a purely phenomenological Michaelis–Menten-like approach that has no connection with underlying chemical states.…”

“…We recently introduced a new theoretical framework to investigate the mechanisms of secondary-active transport. , This is a minimal chemical-kinetic approach that takes into account the most relevant chemical states and transitions, allowing us to obtain explicit expressions for dynamic properties of antiporters and symporters. This method is filling a theoretical gap between the computational models that concentrate on structure changes during the translocation and phenomenological structureless models that are frequently utilized to analyze the experimental data on dynamics.…”

“…Let us consider a chemical-kinetic model, presented in Figure , that has been successfully applied to describe the molecular translocation processes in antiporters. , There are two types of molecules in the system. Molecules of type A and B have their concentrations above the membrane (outside of cell) as c A and c B , respectively, and the concentrations of these species below the membrane (inside the cell) are equal to c A ′ and c B ′ , respectively.…”