Abstract
Water is at the heart of almost all biological phenomena, without which no life that we know of would have been possible. It is a misleadingly complex liquid that exists in near coexistence with the vapor phase under ambient conditions. Confinement within a hydrophobic cavity can tip this balance enough to drive a cooperative dewetting transition. For a nanometer-scale pore, the dewetting transition leads to a stable dry state that is physically open but impermeable to ions. This phenomenon is often referred to as hydrophobic gating. Numerous transmembrane protein ion channels have now been observed to utilize hydrophobic gating in their activation and regulation. Here, we review recent theoretical, simulation, and experimental studies that together have started to establish the principles of hydrophobic gating and discuss how channels of various sizes, topologies, and biological functions can utilize these principles to control the thermodynamic properties of water within their interior pores for gating and regulation. Exciting opportunities remain in multiple areas, particularly on direct experimental detection of hydrophobic dewetting in biological channels and on understanding how the cell may control the hydrophobic gating in regulation of ion channels.
Highlights
Water is the “matrix of life,” without which no life, that we know of, would be possible.1 With unique characteristics as a polar, protic, and amphoteric substance, water can act as both a reagent and a solvent in biological processes
Confinement in a hydrophobic pore could shift the equilibrium toward the vapor phase, leading to a cooperative dewetting transition of the pore
The vapor phase created a large energy barrier to block the passage of ions through the pore, which is known as hydrophobic gating
Summary
Water is the “matrix of life,” without which no life, that we know of, would be possible. With unique characteristics as a polar, protic, and amphoteric substance, water can act as both a reagent and a solvent in biological processes. The density fluctuation near a hydrophobic surface is significantly elevated This Perspective briefly reviews how this unique thermodynamic property of water can give rise to complex phase dynamics in confinement and discusses recent progresses in understanding how transmembrane (TM) protein ion channels may control phase transitions of confined water within their conductive pathways for channel gating and regulation. These experiments showed that the depletion layer was on the order of one water molecule (∼2 Å–4 Å) in thickness and independent of whether or not the water was degassed While these experiments did not directly detect density fluctuations, molecular dynamics (MD) simulations have largely confirmed the existence of nm-scale density fluctuations near various hydrophobic model surfaces and provided important insights into how non-ideal surface properties such as the presence of hydrophilic groups and roughness modulated the liquid–vapor coexistence.. While these experiments did not directly detect density fluctuations, molecular dynamics (MD) simulations have largely confirmed the existence of nm-scale density fluctuations near various hydrophobic model surfaces and provided important insights into how non-ideal surface properties such as the presence of hydrophilic groups and roughness modulated the liquid–vapor coexistence. Hydrophobic dewetting likely creates a major driving force that facilitates various biophysical processes including protein folding, binding, and assembly. For example, atomistic simulations were able to directly observe partial and complete dewetting transitions during the folding of a multidomain protein and self-assembly of the melittin tetramers, respectively
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