Ion channels

Abstract:

Interactions between ions and water at hydrophobic interfaces within ion channels and nanopores are suggested to play a key role in the movement of ions across biological membranes. Previous molecular-dynamics simulations have shown that anion affinity for aqueous/hydrophobic interfaces can be markedly influenced by including polarization effects through an electronic continuum correction. Here, we designed a model biomimetic nanopore to imitate the polar pore openings and hydrophobic gating regions found in pentameric ligand-gated ion channels. Molecular-dynamics simulations were then performed using both a non-polarizable force field and the electronic-continuum-correction method to investigate the behavior of water, Na+, and Cl- ions confined within the hydrophobic region of the nanopore. Number-density distributions revealed preferential Cl- adsorption to the hydrophobic pore walls, with this interfacial layer largely devoid of Na+. Free-energy profiles for Na+ and Cl- permeating the pore also display an energy-barrier reduction associated with the localization of Cl- to this hydrophobic interface, and the hydration-number profiles reflect a corresponding reduction in the first hydration shell of Cl-. Crucially, these ion effects were only observed through inclusion of effective polarization, which therefore suggests that polarizability may be essential for an accurate description for the behavior of ions and water within hydrophobic nanoscale pores, especially those that conduct Cl-.

Abstract:

Water molecules within biological ion channels are in a nanoconfined environment and therefore exhibit behaviors which differ from that of bulk water. Here, we investigate the phenomenon of hydrophobic gating, the process by which a nanopore may spontaneously dewet to form a "vapor lock" if the pore is sufficiently hydrophobic and/or narrow. This occurs without steric occlusion of the pore. Using molecular dynamics simulations with both rigid fixed-charge and polarizable (AMOEBA) force fields, we investigate this wetting/dewetting behavior in the transmembrane protein 175 ion channel. We examine how a range of rigid fixed-charge and polarizable water models affect wetting/dewetting in both the wild-type structure and in mutants chosen to cover a range of nanopore radii and pore-lining hydrophobicities. Crucially, we find that the rigid fixed-charge water models lead to similar wetting/dewetting behaviors, but that the polarizable water model resulted in an increased wettability of the hydrophobic gating region of the pore. This has significant implications for molecular simulations of nanoconfined water, as it implies that polarizability may need to be included if we are to gain detailed mechanistic insights into wetting/dewetting processes. These findings are of importance for the design of functionalized biomimetic nanopores (e.g., sensing or desalination) as well as for furthering our understanding of the mechanistic processes underlying biological ion channel function.

Abstract:

Water molecules within biological ion channels are in a nanoconfined environment and therefore exhibit behaviors which differ from that of bulk water. Here, we investigate the phenomenon of hydrophobic gating, the process by which a nanopore may spontaneously dewet to form a “vapor lock” if the pore is sufficiently hydrophobic and/or narrow. This occurs without steric occlusion of the pore. Using molecular dynamics simulations with both rigid fixed-charge and polarizable (AMOEBA) force fields, we investigate this wetting/dewetting behavior in the transmembrane protein 175 ion channel. We examine how a range of rigid fixed-charge and polarizable water models affect wetting/dewetting in both the wild-type structure and in mutants chosen to cover a range of nanopore radii and pore-lining hydrophobicities. Crucially, we find that the rigid fixed-charge water models lead to similar wetting/dewetting behaviors, but that the polarizable water model resulted in an increased wettability of the hydrophobic gating region of the pore. This has significant implications for molecular simulations of nanoconfined water, as it implies that polarizability may need to be included if we are to gain detailed mechanistic insights into wetting/dewetting processes. These findings are of importance for the design of functionalized biomimetic nanopores (e.g., sensing or desalination) as well as for furthering our understanding of the mechanistic processes underlying biological ion channel function.