Molecular Dynamics Simulations Based on Polarizable Models Show that Ion Permeation Interconverts between Different Mechanisms as a Function of Membrane Thickness

Abstract

Different mechanisms have been proposed to explain the permeation of charged compounds through lipid membranes. Overall, it is expected that an ion-induced defect permeation mechanism, where substantial membrane deformations accompany ion movement, should be dominant in thin membranes but that a solubility–diffusion mechanism, where ions partition into the membrane core with large associated dehydration energy costs, becomes dominant in thicker membranes. However, while this physical picture is intuitively reasonable, capturing the interconversion between these two permeation mechanisms in molecular dynamics (MD) simulations based on atomic models is challenging. In particular, simulations relying on nonpolarizable force fields are artificially unfavorable to the solubility–diffusion mechanism, as induced polarization of the nonpolar hydrocarbon is ignored, causing overestimated free energy costs for charged molecules to enter into this region of the membrane. In this study, all-atom MD simulations based on nonpolarizable and polarizable force fields are used to quantitatively characterize the permeation process for the arginine side chain analog methyl-guanidinium through bilayer membranes of mono-unsaturated phosphatidylcholine lipids with and without cholesterol, resulting in thicknesses spanning from ∼24 to ∼42 Å. With simulations based on a nonpolarizable force field, ion translocation can take place solely through an ion-induced defect mechanism, with free energy barriers increasing linearly from 14 to 40 kcal/mol, depending on the thickness. However, with simulations based on a polarizable force field, ion translocation is predominantly dominated by an ion-induced defect mechanism in thin membranes, which progressively converts to a solubility–diffusion mechanism as the membranes get thicker. The transition between the two mechanisms occurs at a thickness of ∼29 Å, with lipid tails of 22 or more carbon atoms. This situation appears to represent the upper limit for ion-induced defect permeation within the current polarizable models. Beyond this thickness, it becomes energetically preferable for the ion to dehydrate and partition into the membrane corea phenomenon that cannot be captured using the nonpolarizable models. Induced electronic polarizability therefore leads not just to a shift in permeation energetics but to an interconversion between two strikingly different physical mechanisms. The result highlights the importance of induced polarizability in modeling lipid membranes.

Influence of water models on water movement through AQP1

“…Simulating polarizable models require a considerable increase in computational effort, and to date their application has generally been limited to somewhat simpler membrane 60 and channel systems 36,61 . We therefore have decided to first understand the basic features of water transport through AQP1, using only non-polarizable models.…”

Water Nanoconfined in a Hydrophobic Pore: Molecular Dynamics Simulations of Transmembrane Protein 175 and the Influence of Water Models

“…g . simulations of the interactions of ions with lipid bilayer membranes, 33 simple model ion channels e . g .…”

“…In particular, there are indications that the use of more sophisticated water models such as polarizable water models (the dipole moment of which will be responsive to changes in local environment) may be required to capture more adequately the interactions within hydrophobic gates. Although polarizable models are more computationally expensive, the development of more powerful computing facilities and of improved software enables the use of such models for complex biological systems. , Thus, recent studies have explored the influence of polarizable models on, for example, simulations of the interactions of ions with lipid bilayer membranes, simple model ion channels, and on electric field strength within the active site of an enzyme . The effect of polarizable water models within synthetic nanoconfined environments under an electric field has also been investigated, with the conclusion that polarizability can affect the structure and dynamics of the systems. − Various rigid fixed-charge water models have also been assessed for ligand binding in host/guest systems and for water behavior in peptide nanotubes …”

“…Although polarizable models are more computationally expensive, the development of more powerful computing facilities and of improved software enables the use of such models for complex biological systems. 31,32 Thus, recent studies have explored the influence of polarizable models on, for example, simulations of the interactions of ions with lipid bilayer membranes, 33 simple model ion channels, 34 and on electric field strength within the active site of an enzyme. 35 The effect of polarizable water models within synthetic nanoconfined environments under an electric field has also been investigated, with the conclusion that polarizability can affect the structure and dynamics of the systems.…”

Water Nanoconfined in a Hydrophobic Pore: MD Simulations and Water Models

“…Thus, recent studies have explored the influence of polarisable models on e.g. simulations of the interactions of ions with lipid bilayer membranes 30 and with simple model ion channels e.g. 31 .…”