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The Cathedral

Overall Purpose & General Approach

Imagine a medical instrument similar in scale and function to a Magnetic Resonance Imager (MRI). The instrument would be able to observe disease within the body, and then, additionally direct the healing process without drugs or surgical intervention.  A medical instrument conforming to this vision would employ a field capable of penetrating the spatial depths and organs of the body.  It would also have the capability for manipulating and directing the molecular engines and mechanisms, i.e., proteins and enzymes, of the organism.  There are only a few energy fields available to science.  The electric field appears to offer the best means for achieving the proposed instrument.

Electrical energy is the most important physical energy in our daily lives.  It powers our homes and is responsible for carrying information on our telephones and the internet.  What if electrical energy can be used to derive a greater understanding of our bodies and health?  What if the electric field is the key to understanding the deeper aspects of life within the disciplines of biophysics, biochemistry, molecular biology, microbiology, proteomics, genetics, medicine and life, itself?

The interaction of electric fields with molecules is known as dielectrics.  Dielectric materials have been studied since the mid 1800’s.  This discipline should be applicable to the modern understanding of proteins using modern electronic and computational techniques.  An electric field appears to offer the greatest opportunity for directly observing and categorizing larger scale sub-domains, called structural motifs, within a protein.  Such instrumentation would be comparable to “current arts” in biochemistry, i.e., Nuclear Magnetic Resonance (NMR) and Infra-Red (IR) Spectroscopy.  The dielectric responses from proteins will lead to relaxation and resonance signatures.  Such signatures could direct an electric waveform to manipulate protein function and catalysis, thereby stimulating the body to heal.

Spectroscopy allows observation of the frequency response of an electric field with matter.  For example, infra-red (IR) spectroscopy uses the response of molecular vibrations of bonded atoms to an applied electric field.  Essentially, the bonded atoms absorb energy from the applied electric field.  IR spectroscopy allows for the observation of the absorbed energy.  Early developers of IR spectroscopy attributed each distinct frequency response to various bond stretches, bends, and rotations to create a reproducible catalog of atomic responses within the molecule.  The IR table of responses is well-known to any second-year chemistry student and synthetic research chemist.  For, when a peak is observed, we can attribute that response to a certain atomic motion, or organic functional group, within the molecule.  Two examples are the carbon-hydrogen stretch in methane and the amide bond in peptides.  Therefore, IR Spectroscopy has provided modern scientists with a standard, reliable, and routine technique for studying molecular structures and mechanisms.

Dielectric spectroscopy encompasses much lower frequencies, microwave and lower, than IR spectroscopy.  It offers the potential for observing larger structural domains within molecules, or whole molecular responses and processes.  Dielectric spectroscopy is based on charge differentials, or dipoles, interacting with the applied electric field.  Dipoles can have a very local field-of-view, focusing on single atoms, larger sub-domains within molecules, or whole molecular responses.  Each dimension will respond differently to the applied electric field leading to a categorization of molecular dipolar responses.  The proposed dielectric instrumentation development is similar to early IR spectroscopic development.

Proteins are large molecules, composed of thousands of atoms, which possess large sub-domains called structural motifs.  These prevalent motifs, such as a-helices and b-sheets, have been studied for decades.  They possess very definite dipolar characteristics.  For instance, a particular protein is composed of eight a-helical regions, but another protein has three a-helical and four b-sheet regions.  Each region has different dipolar characteristics which should be directly observable with dielectric spectroscopy.

It is the objective of this project to build dielectric spectrometers and develop the techniques for studying the intramolecular dipolar responses of structural motifs within peptides and proteins.  Such studies are analogous to using an electrical surgical knife to probe the internal molecular structure, or “organs”, of peptides and proteins.  Each motif should resonate at a particular frequency complying with that of the applied electric field.  This will provide a unique “fingerprint” for the relaxation or resonance signature.  The categorized signatures will allow researchers to introduce complex electric field waveforms, pulses, and wave packets to influence and manipulate the motifs of the protein.  This will control the structural and catalytic nature of the protein without invasive methods, such as drug or surgical interventions.

Practical Applications

In the same way IR Spectroscopy is a pervasive and routine laboratory technique, we envision the PDP as developing the instrumentation and techniques to create a catalog of dielectric responses for characterizing the secondary structure and intramolecular structural motifs of proteins.  The characterization of such secondary structure will include intrinsic structural and intra- and interchain dynamics of proteins.  Therefore, this endeavor would provide such instrumentation to the college student or research scientist for studying proteins as routinely as studying alkanes with IR Spectroscopy.

For example, a scientist would be able to see the transitions of an a-helical peptide to a random coil by changing the temperature, pH, or salinity of the solution as denaturation occurs.  These initial studies would extend to observing the hydration layers in and around a large complex protein.  Then, allowing the scientist to see the individual structural motifs and their interchain interactions under varying environmental conditions.  This basic understanding would advance the fields of biophysics and biochemistry.

These studies would form a basis for frequency-dependent markers of the intrinsic intramolecular dielectric response of peptides and proteins.  A catalog of markers would allow for the qualitative and quantitative observation of markers, and the transitions from one marker to the next.  This potential avenue for dielectric instrumentation would advance the science of proteomics; or, the identification, assembly, and static and dynamic characterization of all proteins involved in a particular anabolic or catabolic pathway.

The dielectric markers and proteomic instrumentation would allow, for example, a scientist to study the post-translational modification leading to the completely assembled and functional protein or enzyme, or the conformational changes of an enzyme during a reaction, a membrane bound passive ion channel, or an active protein pump.  The scientist will have the tools to study the intramolecular structural transitions of the protein as its carrier passes through the channel. 

Huge macromolecules, such as immunoglobins, can be structurally, dynamically, or conformationally studied with such a dielectric proteomic instrument.  Such macromolecular studies would allow for organelle or cellular studies.  The instrumentation and studies can, for example, contribute to sickle cell versus non-sickle cell diagnosis and drug treatment.  The lipoprotein precursors of cardiovascular condition and treatment can be traced through the dielectric proteomic instrumentation.

A scientist would be able to see how a drug affects the conformational and transitional states of a protein in its natural aqueous environment.  The low-energy non-evasive, and eventually in vivo, technique will dramatically affect medicine and pharmaceuticals.  Perhaps, the technique will lead to directly manipulating single proteins, or sets of proteins, within the body to perform cellular repair, thus inducing the healing process.

Or, once the dynamical processes of protein structure is better understood, then bio- and nanoengineers can synthesize proteins, such as synthetic blood, and molecular machines that are ten million times smaller than your finger nail, but designed and built to perform a specific task.

Since the pure research endeavor of the PDP is so profound, the practical applications are far reaching.  The primary focus of the PDP at this point, is to successfully develop the instrumentation for the proper and reproducible categorizing of the secondary structure and intramolecular structural motifs of peptides and proteins.  Such an instrument would profoundly affect our biophysical, biochemical, and proteomic understanding of living systems, and consequently affect, micro- and molecular cell biology, immunology, endocrinology, pharmacology, bioengineering, and nanotechnology.

Current Project Status

The first generation Phase I Dielectric Spectrometer (P1DS) with a frequency range of 1 mHz to 250 kHz, has been built and tested in my personal laboratory.  It has generated uncompromising results for gelatin, myoglobin, and hemoglobin.  However, the electronics, sample holders, experimental controls, computer hardware and software must be upgraded to see deeper into the proteins.  Phase II through IV Dielectric Spectrometers are currently being developed to encompass a frequency range of 1 mHz to 15 GHz.  These three dielectric spectrometers will provide greater stability, sensitivity, frequency range, and reproducibility then has ever been achieved so far.