Paolo Marracino

Feasibility for Microwaves Energy to Affect Biological Systems Via Nonthermal Mechanisms: A Systematic Approach

The understanding of possible nonthermal bio-effects has been an open question during the last five decades. In this paper, the authors present a critical literature review of the models of the interaction mechanisms, together with an overview of all the publications finding positive results for in vitro and in vivo studies. The systematic approach consisted of pooling together the positive studies on the basis of the endpoints and the biological systems, to identify specific plausible targets of the action of the electromagnetic fields and the related pathways. Such a classification opens the way to the discussion of some hypotheses of interaction mechanisms considered as first transduction step. The authors conclude that only through a multiscale methodology it is possible to perform a comprehensive study of the nonthermal effects, based on affordable and realistic in silico models.

Effect of high exogenous electric pulses on protein conformation: myoglobin as a case study.

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 ultrashort 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 molecule in water exposed to pulsed and static electric fields, ranging from 10(8) to 10(9) V/m, compared to data with unexposed conditions. We have found that the highest intensity (10(9) V/m) produced a fast transition (occurring within a few hundreds of picoseconds) between folded and unfolded states, as inferred by secondary structures and geometrical analysis. Fields of 10(8) V/m, on the contrary, produced no significant denaturation, although a relevant effect on the protein dipolar behavior was detected.

Modeling of Chemical Reactions in Micelle: Water-Mediated Keto-Enol Interconversion As a Case Study

The effect of a zwitterionic micelle environment on the efficiency of the keto-enol interconversion of 2-phenylacetylthiophene has been investigated by means of a joint application of experimental and theoretical/computational approaches. Results have revealed a reduction of the reaction rate constant if compared with bulk water essentially because of the different solvation conditions experienced by the reactant species, including water molecules, in the micelle environment. The slight inhibiting effect due to the application of a static electric field has also been theoretically investigated and presented.

Dipolar response and hydrogen-bond kinetics in liquid water in square-wave time-varying electric fields

Non-equilibrium molecular dynamics simulations of liquid water have been performed at 298 K in the presence of external time-varying electric fields, approximating a square wave, of varying peak intensity (0.005–0.1 V/Å) in the microwave to far-infrared frequency range (20–500 GHz). Significant non-thermal field effects were noted in terms of dipolar response and acceleration of hydrogen-bond kinetics. The coupling between the total dipole moment and the external field has been investigated and autocorrelation functions (ACFs) of both the total dipole moment and the average of the individual molecular dipole moment along the laboratory axis of the applied fields exhibited coupling, with the former showing a stronger coupling and the latter showing coupling to lower magnitude fields. The maximum alignment achieved has been computed as a function of field intensities and frequencies: the lower frequencies show a greater maximum alignment as the system had more time within each field cycle to respond. The normalised probability distribution and the hydrogen-bond ACFs have been computed: the ACF showed a clear effect over shortening the hydrogen-bond relaxation time. The field effects over the molecules’ transitions from four to five hydrogen bonds have been computed. There was an enhancement of fewer molecules undergoing transitions and a dampening for a larger proportion of molecules, depending on the external fields’ periods.

Modeling triplet flavin-indole electron transfer and interradical dipolar interaction: a perturbative approach

A benchmark biochemical reaction is here theoretically investigated by means of a perturbative approach in order to model each reaction step. The reaction is the flavin-indole electron transfer, involving also a spin-state relaxation of the ionic complex. The whole reaction path is modeled and the kinetics of the process is studied. The dipolar interaction between the two radicals is explicitly considered during the dynamic evolution of the system in order to investigate the proper conditions for the triplet-to-singlet transition to occur.

Water response to intense electric fields: A molecular dynamics study

This paper investigated polarization properties of water molecules in close proximity to an ionic charge in the presence of external electric fields by using an approach based on simulations at the atomic level. We chose sodium and chloride ions in water as examples of dilute ionic solutions and used molecular dynamics simulations to systematically investigate the influence of an external static electric field on structural, dipolar, and polarization properties of water near charged ions. Results showed that a threshold electric field higher than 10(8) V/m is needed to affect water polarization and increase mean dipole moment of water molecules close to the ion. A similar threshold holds for water permittivity profiles, although a field 10× higher is needed to ensure that water permittivity is almost constant independently of the position close to the ion. Electric fields of such intensities can greatly enhance polarizability of water in hydration shells around ions.

Signal transduction on enzymes: the Effect of electromagnetic field stimuli on superoxide dismutase (SOD)

Protein functions and characteristics can highly differ from physiological conditions in presence of chemical, mechanical or electromagnetic stimuli. In this work we provide a rigorous picture of electric field effects on proteins behavior investigating, at atomistic details, the possible ways in which an external signal can be transduced into biochemical effects. Results from molecular dynamics (MD) simulations of a single superoxidismutase (SOD) enzyme in presence of high exogenous alternate electric fields will be discussed.

Geometrical Characterization of an Electropore from Water Positional Fluctuations

We present here a new method for calculating the radius of a transmembrane pore in a phospholipid bilayer. To compare size-related properties of pores in bilayers of various compositions, generated and maintained under different physical and chemical conditions, reference metrics are needed. Operational metrics can be associated with some observed behavior. For example, pore size can be defined by the largest object that will pass through the length of the pore. The novelty of the present approach resides in the characterization of electropore geometry via a statistical approach, based on essential dynamics rules. We define the pore size geometrically with an algorithm for determining the pore radius. In particular, we extract the radius from the tri-dimensional surface of a defined pore region. The method is applied to a pore formed in a phospholipid bilayer by application of an external electric field. Although the details described here are specific for lipid pores in molecular dynamics simulations, the method can be generalized for any kind of pores for which appropriate structural information is available.

Human Aquaporin 4 Gating Dynamics under Perpendicularly-Oriented Electric-Field Impulses: A Molecular Dynamics Study

Human aquaporin 4 has been studied using molecular dynamics (MD) simulations in the absence and presence of pulses of external static electric fields. The pulses were 10 ns in duration and 0.012–0.065 V/Å in intensity acting along both directions perpendicular to the pores. Water permeability and the dipolar response of all residues of interest (including the selectivity filter) within the pores have been studied. Results showed decreased levels of water osmotic permeability within aquaporin channels during orthogonally-oriented field impulses, although care must be taken with regard to statistical certainty. This can be explained observing enhanced “dipolar flipping” of certain key residues, especially serine 211, histidine 201, arginine 216, histidine 95 and cysteine 178. These residues are placed at the extracellular end of the pore (serine 211, histidine 201, and arginine 216) and at the cytoplasm end (histidine 95 and cysteine 178), with the key role in gating mechanism, hence influencing water permeability.

Technology and design of innovative flexible electrode for biomedical applications

The electrochemotherapy is an effective treatment that requires the application of an intense electric field to the tumoral tissue to open the cellular membrane and deliver drugs. This work will present the results of the ongoing research project, showing a new technology and design geometry that allows to realize flexible electrodes able to wrap biological tissues bringing the necessary electric field intensity for the electroporation of cells to reach a unique penetration depth to the centimeter range. The flexible electrode is realized by conversion of porous silicon into nano-porous metals (copper and/or gold) filled by a biocompatible thermoplastic polymer.