Limits...
Free energy for the permeation of Na(+) and Cl(-) ions and their ion-pair through a zwitterionic dimyristoyl phosphatidylcholine lipid bilayer by umbrella integration with harmonic fourier beads.

Khavrutskii IV, Gorfe AA, Lu B, McCammon JA - J. Am. Chem. Soc. (2009)

Bottom Line: We find that the free energy barrier to permeation reduces in the order Na(+)-Cl(-) ion-pair (27.6 kcal/mol) > Cl(-) (23.6 kcal/mol) > Na(+) (21.9 kcal/mol).Despite the fact that the bilayer boosts the Na(+)-Cl(-) ion binding free energy by as high as 17.9 kcal/mol near its center, ion-pairing between such hydrophilic ions as Na(+) and Cl(-) does not assist their permeation.This work establishes general computational methodology to address ion-pairing in fluid anisotropic media and details the ion permeation mechanism on atomic level.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, University of CaliforniaSan Diego, La Jolla, California 92093-0365, USA. ikhavru@mccammon.ucsd.edu

ABSTRACT
Understanding the mechanism of ion permeation across lipid bilayers is key to controlling osmotic pressure and developing new ways of delivering charged, drug-like molecules inside cells. Recent reports suggest ion-pairing as the mechanism to lower the free energy barrier for the ion permeation in disagreement with predictions from the simple electrostatic models. In this paper we quantify the effect of ion-pairing or charge quenching on the permeation of Na(+) and Cl(-) ions across DMPC lipid bilayer by computing the corresponding potentials of mean force (PMFs) using fully atomistic molecular dynamics simulations. We find that the free energy barrier to permeation reduces in the order Na(+)-Cl(-) ion-pair (27.6 kcal/mol) > Cl(-) (23.6 kcal/mol) > Na(+) (21.9 kcal/mol). Furthermore, with the help of these PMFs we derive the change in the binding free energy between the Na(+) and Cl(-) with respect to that in water as a function of the bilayer permeation depth. Despite the fact that the bilayer boosts the Na(+)-Cl(-) ion binding free energy by as high as 17.9 kcal/mol near its center, ion-pairing between such hydrophilic ions as Na(+) and Cl(-) does not assist their permeation. However, based on a simple thermodynamic cycle, we suggest that ion-pairing between ions of opposite charge and solvent philicity could enhance ion permeation. Comparison of the computed permeation barriers for Na(+) and Cl(-) ions with available experimental data supports this notion. This work establishes general computational methodology to address ion-pairing in fluid anisotropic media and details the ion permeation mechanism on atomic level.

Show MeSH
Normalized uncorrected histograms for the Na+−Cl− distance distributions as a function of the bilayer permeation depth. The horizontal white line indicates the zero on the z-axis. Color-coding was done on a logarithmic scale to accentuate the SSIP relative to CIP by exponentiation of the normalized densities to the 1/5 power. The plot was generated with Matlab7.6 software.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2651636&req=5

fig3: Normalized uncorrected histograms for the Na+−Cl− distance distributions as a function of the bilayer permeation depth. The horizontal white line indicates the zero on the z-axis. Color-coding was done on a logarithmic scale to accentuate the SSIP relative to CIP by exponentiation of the normalized densities to the 1/5 power. The plot was generated with Matlab7.6 software.

Mentions: In the simulations of the ion-pair permeation across the bilayer, the Na+ and Cl− ions are free to dissociate according to the underlying free energy. To assess the effect of the DMPC lipid bilayer on the free energy of ion-pairing, we compute interionic distance histograms for each of the 67 beads in the Na+−Cl− ion-pair permeation PMF. Although the limited sampling prevents us from converting this data into the corresponding Na+−Cl− distance PMFs, the observed changes in the uncorrected distance distribution along the bilayer normal provide useful information. Thus, Figure 3 shows the top view of a 3D plot of the Na+−Cl− distance distribution histograms with respect to position of the center of mass of the Na+−Cl− ion-pair in the bilayer.


Free energy for the permeation of Na(+) and Cl(-) ions and their ion-pair through a zwitterionic dimyristoyl phosphatidylcholine lipid bilayer by umbrella integration with harmonic fourier beads.

Khavrutskii IV, Gorfe AA, Lu B, McCammon JA - J. Am. Chem. Soc. (2009)

Normalized uncorrected histograms for the Na+−Cl− distance distributions as a function of the bilayer permeation depth. The horizontal white line indicates the zero on the z-axis. Color-coding was done on a logarithmic scale to accentuate the SSIP relative to CIP by exponentiation of the normalized densities to the 1/5 power. The plot was generated with Matlab7.6 software.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651636&req=5

fig3: Normalized uncorrected histograms for the Na+−Cl− distance distributions as a function of the bilayer permeation depth. The horizontal white line indicates the zero on the z-axis. Color-coding was done on a logarithmic scale to accentuate the SSIP relative to CIP by exponentiation of the normalized densities to the 1/5 power. The plot was generated with Matlab7.6 software.
Mentions: In the simulations of the ion-pair permeation across the bilayer, the Na+ and Cl− ions are free to dissociate according to the underlying free energy. To assess the effect of the DMPC lipid bilayer on the free energy of ion-pairing, we compute interionic distance histograms for each of the 67 beads in the Na+−Cl− ion-pair permeation PMF. Although the limited sampling prevents us from converting this data into the corresponding Na+−Cl− distance PMFs, the observed changes in the uncorrected distance distribution along the bilayer normal provide useful information. Thus, Figure 3 shows the top view of a 3D plot of the Na+−Cl− distance distribution histograms with respect to position of the center of mass of the Na+−Cl− ion-pair in the bilayer.

Bottom Line: We find that the free energy barrier to permeation reduces in the order Na(+)-Cl(-) ion-pair (27.6 kcal/mol) > Cl(-) (23.6 kcal/mol) > Na(+) (21.9 kcal/mol).Despite the fact that the bilayer boosts the Na(+)-Cl(-) ion binding free energy by as high as 17.9 kcal/mol near its center, ion-pairing between such hydrophilic ions as Na(+) and Cl(-) does not assist their permeation.This work establishes general computational methodology to address ion-pairing in fluid anisotropic media and details the ion permeation mechanism on atomic level.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, University of CaliforniaSan Diego, La Jolla, California 92093-0365, USA. ikhavru@mccammon.ucsd.edu

ABSTRACT
Understanding the mechanism of ion permeation across lipid bilayers is key to controlling osmotic pressure and developing new ways of delivering charged, drug-like molecules inside cells. Recent reports suggest ion-pairing as the mechanism to lower the free energy barrier for the ion permeation in disagreement with predictions from the simple electrostatic models. In this paper we quantify the effect of ion-pairing or charge quenching on the permeation of Na(+) and Cl(-) ions across DMPC lipid bilayer by computing the corresponding potentials of mean force (PMFs) using fully atomistic molecular dynamics simulations. We find that the free energy barrier to permeation reduces in the order Na(+)-Cl(-) ion-pair (27.6 kcal/mol) > Cl(-) (23.6 kcal/mol) > Na(+) (21.9 kcal/mol). Furthermore, with the help of these PMFs we derive the change in the binding free energy between the Na(+) and Cl(-) with respect to that in water as a function of the bilayer permeation depth. Despite the fact that the bilayer boosts the Na(+)-Cl(-) ion binding free energy by as high as 17.9 kcal/mol near its center, ion-pairing between such hydrophilic ions as Na(+) and Cl(-) does not assist their permeation. However, based on a simple thermodynamic cycle, we suggest that ion-pairing between ions of opposite charge and solvent philicity could enhance ion permeation. Comparison of the computed permeation barriers for Na(+) and Cl(-) ions with available experimental data supports this notion. This work establishes general computational methodology to address ion-pairing in fluid anisotropic media and details the ion permeation mechanism on atomic level.

Show MeSH