Molecular Mechanisms of Active Transport in Antiporters: Kinetic Constraints and Efficiency

Abstract

A vital role in supporting successful functioning of biological cells is played by membrane channels called antiporters. These channel proteins utilize the concentration gradient of one type of species to move another type of species in the opposite direction and against their concentration gradient. It is believed that antiporters operate via alternating conformational transitions that expose these proteins to different sides of the membrane, and that only thermodynamics controls the activation of these channels. Here we explicitly investigate a chemical-kinetic model of antiporters to argue that there are additional kinetic constraints that need to be satisfied for these channels to be operational. This implies that kinetics and not thermodynamics governs the functioning of antiporters. In addition, the efficiency of antiporters is analyzed and the most optimal operating conditions are discussed. Our theoretical analysis clarifies some important aspects of the molecular mechanisms of biological membrane transport.

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

“…But it is known that although symporters and antiporters share many similar properties, there are some differences in the mechanisms of translocation adopted by these membrane channels. 20 It will be interesting to explore all these possibilities in more advanced theoretical studies, and it will be also critical to test the obtained theoretical predictions in experimental studies.…”

“…In this case, the driving force from the translocations of molecules A will be smaller due to the leakage current. 20 At large concentrations c A , the relative effect of the leakage current is negligible. It is much easier to explain the effect of mutations on the catalytic ability of the antiporter (Figure 2d).…”

“…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.…”