Molecular dynamics (MD) has been shown to be a useful tool for unveiling many aspects of pore formation in lipid membranes under the influence of an applied electric field. However, the study of the structure and transport properties of electropores by means of MD has been hampered by difficulties in the maintenance of a stable electropore in the typically small simulated membrane patches. We describe a new simulation scheme in which an initially larger porating field is systematically reduced after pore formation to lower stabilizing values to produce stable, size-controlled electropores, which can then be characterized at the molecular level. A new method allows the three-dimensional modeling of the irregular shape of the pores obtained as well as the quantification of its volume. The size of the pore is a function of the value of the stabilizing field. At lower fields the pore disappears and the membrane recovers its normal shape, although in some cases long-lived, fragmented pores containing unusual lipid orientations in the bilayer are observed.
[Show abstract][Hide abstract] ABSTRACT: Protein folding and unfolding under the effect of exogenous perturbations remains a topic of great interest, further enhanced by recent technological developments in the field of signal generation that allow the use of intense-ultra short electric pulses to directly interact at microscopic level with biological matter. In this paper we show results from molecular dynamics (MD) simulations of a single myoglobin in water exposed to pulsed and static electric fields, ranging from 108 to 109 V/m, comparing data with unexposed conditions. We have found that the higher intensity (109 V/m) produced a fast transition (occurring within a few hundreds of ps) between folded and unfolded states, as inferred by secondary-structures and geometrical analysis. Fields of 108 V/m, on the contrary, produced no significant denaturation although a relevant effect on the protein dipolar behavior was present.
The Journal of Physical Chemistry B 01/2013; 117(8). DOI:10.1021/jp309857b · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Structural modifications of cell membranes are among the primary
consequences of exposure to intense nanosecond pulsed electric fields.
These alterations can be characterized indirectly by monitoring changes
in electrical conductance or small molecule permeability of artificial
membranes or suspensions of living cells, but direct observations of the
membrane-permeabilizing structures remain out of the reach of
experiments. Molecular dynamics simulations provide an atomically
detailed view on the nanosecond time scale of the sequence of events
that follows the application of an external electric field to a system
containing an aqueous electrolyte and a phospholipid bilayer, a simple
approximation of a cell membrane. This biomolecular perspective, which
correlates with experimental observations of electroporation
(electropermeabilization) in many respects, points to the key role of
water dipoles, driven by the electric field gradients at the membrane
interface, in the initiation and construction of the membrane defects
which evolve into conductive pores. We describe a method for stabilizing
these lipid electropores in phospholipid bilayers, and for
characterizing their stability and ion conductance, and we show how the
properties of these nanoscale structures connect with continuum models
of electroporation and with experimental results.
Proceedings of SPIE - The International Society for Optical Engineering 02/2013; 8585. DOI:10.1117/12.2005996 · 0.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Formation of a water bridge across the lipid bilayer is the first stage of pore formation in molecular dynamic (MD) simulations of electroporation, suggesting that the intrusion of individual water molecules into the membrane interior is the initiation event in a sequence that leads to the formation of a conductive membrane pore. To delineate more clearly the role of water in membrane permeabilization, we conducted extensive MD simulations of water bridge formation, stabilization, and collapse in palmitoyloleoylphosphatidylcholine bilayers and in water-vacuum-water systems, in which two groups of water molecules are separated by a 2.8 nm vacuum gap, a simple analog of a phospholipid bilayer. Certain features, such as the exponential decrease in water bridge initiation time with increased external electric field, are similar in both systems. Other features, such as the relationship between water bridge lifetime and the diameter of the water bridge, are quite different between the two systems. Data such as these contribute to a better and more quantitative understanding of the relative roles of water and lipid in membrane electropore creation and annihilation, facilitating a mechanism-driven development of electroporation protocols. These methods can be extended to more complex, heterogeneous systems that include membrane proteins and intracellular and extracellular membrane attachments, leading to more accurate models of living cells in electric fields.
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