Coherent Excitations Frhlich

Protein conformational states can register dynamic biological information and control the real time functions of cytoplasm. The mechanisms of conformational regulation are not clearly understood, primarily because technology has not (quite) yet reached the nanoscale. Proteins are clearly vibrant, dynamic structures in physiological conditions. A variety of recent techniques (nuclear magnetic resonance, X-ray diffraction, fluorescence depolarization, infrared spectroscopy, Raman and Brillouin laser scattering) have shown that proteins and their component parts undergo conformational motions over a range of time scales from femtoseconds (10-15 sec) to many minutes.

The most significant conformational vibrations are suggested by Harvard's Karplus and McCammon (1984) to be in the middle of this range: nanoseconds. Such fluctuations are appropriate for conformational motion of globular proteins (4 to 10 nanometer diameter), consistent with enzymatic reaction rates and "coupled modes" like solitons. As an example, Karplus and McCammon describe a rotation of a tyrosine ring deep inside a globular protein called bovine pancreatic trypsin inhibitor. The side chain of the amino acid tyrosine includes a six carbon "aromatic" hexagonal ring with an electron resonance cloud. The rotation of the ring has been studied experimentally by nuclear magnetic resonance and Karplus and McCammon have done a computer simulation based on that data which shows the protein changing conformational state as the tyrosine ring rotates 90 degrees. The switch occurs in the nanosecond time scale and is collectively coupled to movement in the polypeptide backbone chain.

Collective nanosecond conformational states have been elegantly woven in a theory of coherent protein excitations by Professor Herbert Fröhlich who presently divides his time between Liverpool University and the Max Planck Institute in Stuttgart. Recognized as a major contributor to the modern theory of superconductivity, Fröhlich turned to the study of biology in the late 1960's and came to several profound conclusions. One is that changes in protein conformation in the nanosecond time scale are triggered by a charge redistribution such as a dipole oscillation within hydrophobic regions of proteins (Fröhlich, 1975). Another Fröhlich (1970) concept is that a set of proteins connected in a common voltage gradient field such as within a membrane or polymer electret such as the cytoskeleton would oscillate coherently at nanosecond periodicity if energy such as biochemical ATP were supplied. Fröhlich's model of coherency can explain long range cooperative effects by which proteins and nucleic acids in biological systems can communicate. A major component of Fröhlich's theory suggests that random supply of energy to a system of nonlinearly coupled dipoles can lead to coherent excitation of a single vibrational mode, provided the energy exceeds a critical threshold. Frequencies of the order of 109 to 1011 Hz are suggested by Fröhlich, who maintains that the single mode appears because all others are in thermal equilibrium. Far reaching biological consequences may be expected from such coherent excitations and long range cooperativity.

Conformation of proteins and their dipole moments in aqueous, physiological environment are dominated by interaction of their charge groups with surrounding water and ions. Some biomolecules may possess excited states with very high dipole moments. These levels, according to Fröhlich, tend to become stabilized (become "metastable states") through internal and external deformations and through displacement of "counter" ions like calcium. Metastable states, which correlate with functional conformations, are thus collective effects involving the molecule and its surroundings. A molecule might be lifted into a metastable state through the action of electric fields, binding of ligands or neurotransmitters, or effects of neighbor proteins. Thus rapid, nanosecond oscillations may become "locked" in specific modes which correspond to useful conformations of a protein. For example an ion channel, receptor, enzyme, or tubulin subunit may stay in one conformational state for relatively long periods, on the order of milliseconds. Fröhlich characterizes these conformations as "metastable" states.

Fröhlich observes that the high electric field of the order of 107 volts per meter maintained in many biological membranes (100 millivolts / 10 nanometers = 107 volts/meter) requires an extraordinary dielectric property of the membrane components including lipids and proteins. Similar requirements would exist for cytoskeletal proteins in an electret. Ordinary material would suffer dielectric breakdown in such fields unless specially prepared. Fröhlich contends the biological evolution of this dielectric strength on a molecular scale must have strong significance. Biological organisms are relatively impervious to effects of electromagnetic radiation, yet can be exquisitely sensitive to it in some circumstances. Some biological functions border on the limit imposed by quantum mechanics. Our eyes are sensitive to single photons and certain fish are sensitive to extremely weak electric fields. Such performances, according to Fröhlich, require the use of collective properties of assemblies of biomolecules and certain types of collective behavior such as coherent vibrations should be expected.

If coherent oscillations representing dipole vibrations within molecular systems do coherently oscillate in the range of 109 to 1011 Hz, it should be possible to excite these modes by electromagnetic radiation. In order to couple and excite the biological vibrations, radiation should be matched to the biological frequency and the wavelength should be large compared to the dimension of the oscillating object. A significant amount of evidence supports this notion. Irradiation of a great variety of biological objects with coherent millimeter waves in the frequency region of 0.5 x 1011 Hz can exert great influences on biological activities provided the power supply lies above a critical threshold (Grundler and Keilman, 1983). According to Fri hlich, the biological effects are not temperature effects. They show very sharp frequency resonances which indicates that localized absorption in very small spatial regions contributes to the biological actions.

The sharp resonance of this sensitive window has a frequency width of about 2 x 108 Hz. The layer of ordered water and ions subjacent to membranes and cytoskeletal structures (the "Debye layer") absorbs in the region of 108 Hz. This suggests that the Debye layer is closely involved with the dynamic functional activities of the biostructures which they surround. Green and Triffet (1985) have modeled propagating waves and the potential for information transfer in the dynamics of the Debye layer immediately beneath membranes and cytoskeletal proteins. They have hypothesized a holographic information medium due to the coherent vibrations in space and time of these biomolecules. The medium they consider is the ordered water and layers of calcium counter ions surrounding the high dipole moments in membranes and biomolecules. Thus they have developed a theory of ionic bioplasma in connection with nonlinear properties which relates to the existence of highly polar metastable states. The small scale and ordering would minimize friction in these activities. Fröhlich observes: "clearly the absence of other frictional processes would present most interesting problems." He suggests the possibility of propagating waves due to the lack of frictional processes ("superconductivity") in the biomolecule itself as well as the layer of ordered water or Debye layer (Kuntz and Kauzmann, 1974). Until recently, superconductivity has been considered to occur only in certain ordered materials at temperatures near absolute zero. Recent discoveries, however, have shown that superconductivity can occur in materials at higher temperatures due apparently to coherent ordering and coupling among localized and collective lattice vibrations (Maddox, 1987; Robinson, 1987).

Expanding on Fröhlich's work, Wu and Austin (1978) conclude that oscillating dipoles within a narrow band of resonance frequencies with large enough coupling constants may be expected to cause strong long range (about 1 micron) attractive forces among dipoles. In a dense microtubule array, 1 cubic micron (one billion cubic nanometers) would encompass about 160,000 tubulin subunits-an array sufficiently large for collective effects.

Evidence for such "long-range" effects have been observed in the behavior of red blood cells. Discoids of eight micron diameter (8 thousand nanometers), red blood cells tend to array themselves in stacks called "Rouleaux formation." Rowlands (1983) has studied Rouleaux formation and found that attractive forces begin when the red cells are about four microns (4 thousand nanometers) apart, a distance several orders of magnitude greater than the range of attractive chemical forces. Rowlands views this behavior as consistent with Fröhlich's coherent excitations and long range cooperativity. Rowlands also projects the significance of Fröhlich's theory to communication in the nervous system.

Rowlands (1983) notes that

A communication band extending from 10 10 to 1011 Hz ... could pack over a million FM radio stations ... or 150,000 television broadcasts ... the action potential may be just a crude fast transmitter of urgent messages ... . Fröhlich vibrations might be transmitted along the membrane of the nerve fibers, but they would be interrupted by action potentials. It is more likely that microtubules in the axon are used.

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