Influence of effective polarization on ion and water interactions within a biomimetic nanopore

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^-.

Figure 1

(A) Schematic of a biomimetic nanopore. The model nanopore has a radius r, such that 0 < r < R_pore. (B) Top-down view of the pore, showing water molecules (blue) restrained to the CNT pore walls (orange) to create the polar regions at each mouth of the pore. The nanopore ends are capped with hydrogen atoms (white). (C) Snapshot of the simulation setup. The biomimetic nanopore is embedded in a palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer (lipid headgroup phosphates in green) and solvated with water (light blue), Cl^- (yellow), and Na⁺ (pink). (D) Pore-radius profile showing the maximum value of R_pore as a function of axial position z (approximately aligned with the simulation snapshot in (C). To see this figure in color, go online.

Figure 2

(A–F) Symmetrized number-density profiles of Cl^- (A and D), Na⁺ (B and E), and water (C and F), with ECC-rescaled ionic charges and a non-polarizable force field for all other atoms, at various salt concentrations. $\rho \left(r\right)/{\text{ρ}}_{\text{b}}$ represents the symmetrized number-density, $\rho \left(r\right)$, sampled from the hydrophobic region of the nanopore (orange section of schematic (Fig. 1A)) and normalized by bulk density, ${\text{ρ}}_{\text{b}}$. The variable r is the radius of the nanopore, which extends from 0 (pore axis) to R_pore (the interface where the salt solution meets the wall of the nanopore). The gray vertical dashed line represents R_pore. To see this figure in color, go online.

Figure 3

(A–F) Symmetrized number-density profiles of Cl^- (A and D), Na⁺ (B and E), and water (C and F), with ECC-rescaled ionic charges and a standard non-polarizable force field for all other atoms, in nanopores of different radii. $\rho \left(r\right)/{\text{ρ}}_{\text{b}}A$ represents the symmetrized number-density, $\rho \left(r\right)$, sampled from the hydrophobic region of the nanopore and normalized by bulk density, ${\text{ρ}}_{\text{b}}$, and internal surface area, $A$, of the nanopore. The vertical dashed lines indicate the interface where the aqueous solution meets the wall of the nanopore (at radius R_pore), colored accordingly for each respective nanopore size. To see this figure in color, go online.

Figure 4

(A and B) Single-ion PMFs profiles for (A) Cl⁻ and B Na⁺ permeating the model nanopore with ECC-rescaled ionic charges (green) and standard non-polarizable force field (yellow). The distance between the ion and the model nanopore center of mass is denoted by z, where z = 0 represents the center of the pore. The solid lines indicate the free-energy profile calculated from the final 5 ns of each umbrella window. Confidence bands were calculated by taking the standard error over independent 1 ns sampling blocks over the time period sampled. The dashed vertical lines denote the extent of the nanopore. To see this figure in color, go online.

Figure 5

Cl^- hydration structure inside radial sections of the hydrophobic region of the pore. (A) Schematic of the hydrophobic region of the pore divided into four 0.175 nm radial sections colored in decreasing shades of blue. (B and D) The proportion of Cl^- with various hydration numbers in defined radial regions with the ECC method (B) and the non-polarizable force field (D). (C) shows the percentage occupancy of each radial section by Cl^-. With ECC (green line), Cl^- spends a significantly greater proportion of time within the interfacial layer, whereas with the non-polarizable force field (orange line), Cl^- tends to occupy regions away from the pore wall. To see this figure in color, go online.

Figure 6

(A) Snapshot of Cl^- partially desolvating to favorably interact with the internal hydrophobic interface of the model nanopore. Cl^- is represented in yellow, and the oxygen atoms of the water molecules from the first and second hydration shells are represented by light and dark blue beads, respectively. (B) Schematic diagram of an induced dipole in Cl^- at a hydrophobic/water interface. Adapted from (99). To see this figure in color, go online.