Molecular Dynamics Simulations to Probe Effects of Ultra-Short, Very-High Voltage Pulses on Cells
Date of Award
Doctor of Philosophy (PhD)
Electrical & Computer Engineering
Ravindra P. Joshi
Richard L. Nuccitelli
Linda L. Vahala
R. James Swanson
The use of very high electric fields (∼ 100kV/cm or higher) with pulse durations in the nanosecond range (Ultra-short) has been a very recent development in bioelectrics. Traditionally, the electric field effects have mostly been confined to: (a) low field, long-duration pulses, and (b) focused mainly on electroporation studies. Thus, aspects such as possible field-induced DNA damage, calcium release, alterations in neuro-transmitters, or voltage-gating have generally been overlooked.
Ultra-short, high-field pulses open the way to targeted and deliberate apoptotic cell killing (e.g., of tumor cells). Though experimental data is very useful, it usually yields information on macroscopic variables that is inherently an average over time and/or space. Measurements often do not provide the molecular level information or details, as might be possible through numerical simulations. Also, the relevance and relative role of underlying physical mechanisms cannot be probed. With developments in computer technology, rapid advances in numerical algorithms for parallel computing, and with increasing computational resources, computer simulations of cellular dynamics and biological phenomena is gaining increasing popularity. A range of simulation methods exist that span the macroscopic continuum approaches (e.g. the Smoluchowski equation), to those based on the semi-classical retarded Langevin and Green's functions, to microscopic-kinetic analyses based on Brownian dynamics or Molecular Dynamics (MD). Here we focus on the MD technique, as it provides the most comprehensive, time-dependent, three-dimensional nanoscale analyses with inclusion of the many-body aspects. This dissertation research presents simulations and analyses of lipid membrane poration and its dynamics, predictions of transport parameters under high-field, non-equilibrium conditions, electric fields effects on DNA, micelle disintegration, protein unfolding and intra-cellular calcium release.
The following results have been found as a result of the application of external electric fields on cells: (a) Poration due to the re-orientation of the lipid molecules within the lipid bilayer, (b) Externalization of charged molecules such as Phosphotidyl Serine (PS), (c) Dramatic lowering of permittivity and diffusion coefficient with spatially structured layering of the membrane nanopore, (d) DNA alignment in the direction of electric field and eventual fragmentation, (e) Calcium release from the endoplasmic reticulum (ER) leading to time-dependent oscillatory waves and (f) Membrane fragmentation upon the application of high external fields.
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"Molecular Dynamics Simulations to Probe Effects of Ultra-Short, Very-High Voltage Pulses on Cells"
(2007). Doctor of Philosophy (PhD), Dissertation, Electrical & Computer Engineering, Old Dominion University, DOI: 10.25777/5dsp-fb87