TY - JOUR

T1 - Simulations of skin barrier function

T2 - free energies of hydrophobic and hydrophilic transmembrane pores in ceramide bilayers

AU - Notman, Rebecca

AU - Anwar, Jamshed

AU - Briels, W. J.

AU - Noro, Massimo G.

AU - den Otter, Wouter K.

PY - 2008/11/15

Y1 - 2008/11/15

N2 - Transmembrane pore formation is central to many biological processes such as ion transport, cell fusion, and viral infection. Furthermore, pore formation in the ceramide bilayers of the stratum corneum may be an important mechanism by which penetration enhancers such as dimethylsulfoxide (DMSO) weaken the barrier function of the skin. We have used the potential of mean constraint force (PMCF) method to calculate the free energy of pore formation in ceramide bilayers in both the innate gel phase and in the DMSO-induced fluidized state. Our simulations show that the fluid phase bilayers form archetypal water-filled hydrophilic pores similar to those observed in phospholipid bilayers. In contrast, the rigid gel-phase bilayers develop hydrophobic pores. At the relatively small pore diameters studied here, the hydrophobic pores are empty rather than filled with bulk water, suggesting that they do not compromise the barrier function of ceramide membranes. A phenomenological analysis suggests that these vapor pores are stable, below a critical radius, because the penalty of creating water-vapor and tail-vapor interfaces is lower than that of directly exposing the strongly hydrophobic tails to water. The PMCF free energy pro. le of the vapor pore supports this analysis. The simulations indicate that high DMSO concentrations drastically impair the barrier function of the skin by strongly reducing the free energy required for pore opening.

AB - Transmembrane pore formation is central to many biological processes such as ion transport, cell fusion, and viral infection. Furthermore, pore formation in the ceramide bilayers of the stratum corneum may be an important mechanism by which penetration enhancers such as dimethylsulfoxide (DMSO) weaken the barrier function of the skin. We have used the potential of mean constraint force (PMCF) method to calculate the free energy of pore formation in ceramide bilayers in both the innate gel phase and in the DMSO-induced fluidized state. Our simulations show that the fluid phase bilayers form archetypal water-filled hydrophilic pores similar to those observed in phospholipid bilayers. In contrast, the rigid gel-phase bilayers develop hydrophobic pores. At the relatively small pore diameters studied here, the hydrophobic pores are empty rather than filled with bulk water, suggesting that they do not compromise the barrier function of ceramide membranes. A phenomenological analysis suggests that these vapor pores are stable, below a critical radius, because the penalty of creating water-vapor and tail-vapor interfaces is lower than that of directly exposing the strongly hydrophobic tails to water. The PMCF free energy pro. le of the vapor pore supports this analysis. The simulations indicate that high DMSO concentrations drastically impair the barrier function of the skin by strongly reducing the free energy required for pore opening.

KW - PERMEATION

KW - BIOMEMBRANES

KW - WATER

KW - NANOPORES

KW - MECHANISM

KW - MOLECULAR-DYNAMICS SIMULATIONS

KW - DIMETHYL-SULFOXIDE

KW - REACTION COORDINATE

KW - CELL-MEMBRANES

KW - LIPID-BILAYERS

U2 - 10.1529/biophysj.108.138545

DO - 10.1529/biophysj.108.138545

M3 - Journal article

VL - 95

SP - 4763

EP - 4771

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 10

ER -