Abstract
We extend the multiscale spatiotemporal heat map strategies originally developed for interpreting molecular dynamics simulations of well-structured proteins to liquids such as lipid bilayers and solvents. Our analysis informs the experimental and theoretical investigation of electroporation, that is, the externally imposed breaching of the cell membrane under the influence of an electric field of sufficient magnitude. To understand the nanoscale architecture of electroporation, we transform time domain data of the coarse-grained interaction networks of lipids and solvents into spatial heat maps of the most relevant constituent molecules. The application takes advantage of our earlier graph-based activity functions by accounting for the contact-forming and -breaking activity of the lipids in the bilayer. Our novel analysis of lipid interaction networks under periodic boundary conditions shows that the disruption of the bilayer, as measured by the breaking activity, is associated with the externally imposed pore formation. Moreover, the breaking activity can be used for statistically ranking the importance of individual lipids and solvent molecules through a bridging between fast and slow degrees of freedom. The heat map approach highlighted a small number of important lipids and solvent molecules, which allowed us to efficiently search the trajectories for any functionally relevant mechanisms. Our algorithms are freely disseminated with the open-source package TimeScapes.
Highlights
Membrane electroporation is a biomedical technique that artificially increases the permeability of cell membranes by applying short electric pulses (Neumann et al, 1982)
molecular dynamics (MD) simulations of single-pore formation under an external electric field have been of considerable interest for some time (Vernier and Ziegler, 2007; Böckmann et al, 2008; Ziegler and Vernier, 2008; Tokman et al, 2013; Kohler et al, 2015)
Over the last several years, we have developed a statistical strategy for transforming MD simulation time series into spatial heat maps
Summary
Membrane electroporation is a biomedical technique that artificially increases the permeability of cell membranes by applying short electric pulses (Neumann et al, 1982). Electroporation by an external electric field is attributed to the opening of discrete nanometer-sized pores in cell membranes: In some plasma and biomedical experiments, pulsed fields have high power (of the order of megavolts per meter) but short duration (of the order of nanoseconds) (Kohler et al, 2015), conditions that are accessible to atomistic molecular dynamics (MD) simulations. Other electroporative applications such as the electroinsertion of xenoproteins or electrofusion of cells are performed in experiments at much lower voltages and over longer time scales; in these cases, statistical theories may bridge between single-event poration times derived from MD simulations and slower experimental kinetics (Böckmann et al, 2008). Polar water molecules are known to play a key driving role in electroporation (Figure 1); no signature for pore initiation has yet been identified (Vernier and Ziegler, 2007; Ziegler and Vernier, 2008; Kohler et al, 2015), and Kohler et al (2015) argued that a statistical framework would be needed for further development
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