Thermodynamics of electromechanical coupling in voltage-gated ion channels

Membrane proteins are uniquely placed at the interface of the internal and external milieu of cells, and many of them unsurprisingly function as signal transducers involved in pathways critical for normal physiological activity. A majority of these membrane proteins have a modular architecture with distinct sensing and catalytic domains. Understanding how information flows from one part of the molecule to another is crucial for developing a detailed molecular-level understanding of their function. Voltage-gated ion channels are a class of such integral membrane proteins found ubiquitously in all kingdoms of life and are involved in both electrical and chemical signaling pathways (Hille, 2001). Members of this superfamily share a common overall architecture wherein a functional unit is made up of four homologous domains arranged symmetrically around a central axis (Bezanilla, 2000; Long et al., 2005a). Each domain comprises six transmembrane segments and a reentrant pore loop, which forms the selectivity filter of the channel (Heginbotham et al., 1994). The segments S1–S4 constitute the voltage-sensing domain, which, as the name suggests, is the principal element for sensing changes in membrane potential (Bezanilla, 2000; Swartz, 2008). The exquisite voltage sensitivity of these proteins is, in large part, due to a distinct cluster of basic residues on the S4 segment (Aggarwal and MacKinnon, 1996; Seoh et al., 1996). The four S5-S6 segments associate to form the functional pore domain through which ions can flux. The S6 segments line the ion permeation pathway, and, on the intracel-lular side, they come together at the bundle crossing to form the activation gate (Liu et al., 1997; del Camino et al., 2000). Although significant progress has been made in developing a structural view of the gating process, the molecular driving forces that underlie these structural transitions remain poorly understood. Structures of channels in various states may suggest possible inter-actors, but experimental validation of these interactions is essential. In this perspective, we will principally focus on the thermodynamics of conformational coupling Correspondence to Baron Chanda: c h a n d a @ w i s c. e d u between the voltage-sensing domain and the gates in the pore domain, a process referred to as electrome-chanical coupling in recent literature. We will critically discuss the current state of knowledge and highlight the challenges in thermodynamic analysis of complex multistate proteins. Defining " conformational coupling " Dependence between two events can be conveniently expressed using conditional probabilities (Ben-Naim, 2010). For …