10-20 Joules as a Neuromolecular Quantum in Medicinal Chemistry: An Alternative Approach to Myriad Molecular Pathways?

Abstract

The myriads of molecular pathways that have been measured to understand the physical bases of neuronal and other cellular functions have exceeded classical comprehension. In the tradition of Bohr and Schrodinger, the hypothesis is developed that molecular pathways are simply epiphenomenal transports of quanta with increments in the order of 10(-20) J. Experimental measurements of photon emissions from cell cultures and the serial steps of phosphorylation in general molecular pathways and transformations in chromophores supported this contention. This discrete value is also associated with action potentials, intersynaptic events, the biophysical bases of membrane potentials, the numbers of action potentials per cell from magnetic energy potential, and the interionic distances around membranes. Consideration of information as discrete increments of energy may allow greater experimental control and external intervention of pathways relevant to medicinal chemistry.

Full text

3094 Current Medicinal Chemistry, 2010, 17, 3094-3098
0929-8673/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.
10-20 Joules as a Neuromolecular Quantum in Medicinal Chemistry: An
Alternative Approach to Myriad Molecular Pathways?
M.A. Persinger*
Behavioural Neuroscience and Biomolecular Science Programs, Biophysics Section, Laurentian University, Sudbury,
Ontario, P3E 2C6, Canada
Abstract: The myriads of molecular pathways that have been measured to understand the physical bases of neuronal and
other cellular functions have exceeded classical comprehension. In the tradition of Bohr and Schrodinger, the hypothesis
is developed that molecular pathways are simply epiphenomenal transports of quanta with increments in the order of 10-20
J. Experimental measurements of photon emissions from cell cultures and the serial steps of phosphorylation in general
molecular pathways and transformations in chromophores supported this contention. This discrete value is also associated
with action potentials, intersynaptic events, the biophysical bases of membrane potentials, the numbers of action potentials
per cell from magnetic energy potential, and the interionic distances around membranes. Consideration of information as
discrete increments of energy may allow greater experimental control and external intervention of pathways relevant to
medicinal chemistry.
Keywords: Neuroquantum, cell membranes, energy, 10-20 J, wave functions, molecular biology.
1. INTRODUCTION
Modern medical and biological sciences have replaced
the perspective of the singularity of the whole organism with
a matrix of multiple and often dissociated molecular path-
ways [1]. From either a correlational or reductionist ap-
proach to biological systems, the fundamental characteristics
and patterns of larger organizations of matter in space-time
reflect the smaller forms. The initial enthusiasm for molecu-
lar biology proposed by Schrödinger [2] as the quintessential
approach to solve the challenges of medicinal biology has
been dampened by the accelerating numbers of molecular
pathways and the plethora of substitutions in these pathways
by which the apparently "same" signalling occurs. In the
frenzy to find "the molecular pathway", today's manifesta-
tion of Paul Erhlich's "magic bullet", we have forgotten
Bohr's [3] suggestion that small amounts of energy involved
with quantum theory mediate the features of cell functions.
There may be an intrinsic approximal unit of energy by
which many if not all molecular pathways relevant to me-
dicinal chemistry operate. One of these "quanta", in the order
of 10-20 J, involves a chain of simple transformations of mat-
ter and energy across biological space and time. Conse-
quently the numbers of multiple pathways and inordinate
numbers of molecules involved with signalling are simply
carriers or epiphenomena whose presence insures the accu-
rate transmission of these digital quanta whose summations
of events are reflected at larger and larger levels of organiza-
tion. The support for the concept lies within the quantitative
convergence with empirical measurements and the internal
consistencies of the magnitudes of energy. Although tradi-
tions within the last few decades have embraced qualitative
perspectives for reviews and developments of concepts, this
paper is written to re-kindle the tradition of presenting the
precise quantitative reasoning to the reader.
*Address correspondence to this author at the Behavioural Neuroscience
and Biomolecular Science Programs, Biophysics Section, Laurentian Uni-
versity, Sudbury, Ontario, P3E 2C6, Canada; Tel: +1 705 675-4824;
Fax: 705 671 3844; E-mail: mpersinger@laurentian.ca
2. GENERAL CELLULAR RAMIFICATIONS
2.1. The Resting Membrane and Action Potential
An action potential whose net change in voltage is
120 mV (1.2 x 10-1 V) imparts to a unit charge of 1.6 x 10-19
As (Coulombs, C) an energy of 2.0 x 10-20 J. This quantum
of energy is mediated from the initial transduction of ex-
traneuronal energy to action potentials and then through the
release of contents from presynaptic vesicles which in turn
initiates changes within dendrites and soma of the stimulated
neuron. This energy is equivalent to the value required to
stack one base on a RNA ribbon. According to Wei [4] the
duration of this addition and of the action potential is about 1
msec.
This quantum of 10-20 J is also maintained between the
ions within the narrow circumferential shell of about 0.6 nm
[5] associated with cell's resting membrane potential. The
width of the ion channel can be seen as a topologically punc-
tate protrusion of this width through the cell membrane. Em-
pirical measurements indicate that the capacitance of cell
membranes for most neurons and glial cells are within 10%
of 1 microF/cm2. Assuming a resting membrane potential
difference of 70 mV across the membrane, the numbers of
ions within this thin band can be calculated.
The surface area of a 10 um (micrometer) cell is (4pi r2)
or 12.56 x .25 x 10-8 cm2. With q (charge)=voltage times
capacitance, then 70 x 10-3 V x 1 x 10-6 F/cm2 is 7 x 10-8
C/cm2. Hence a cell with a diameter of 10 um would display
a charge of 3.14 x 10-6 cm2 times 7 x 10-8 C/cm2 or 2.20 x 10-
13 C. Because each unit charge is 1.61 x 10-19 C, a total of 2 x
106 molecules and their charges contribute to the resting
membrane potential.
The area occupied by each charge on the cell surface, as-
suming a thickness of only 1 charge within the approxi-
mately 1 nm shell, would be (3.14 x 10-6 cm2) divided by 2 x
106 particles or 1.57 x 10-12 cm2/charge. The square root of
that value is the average distance between charges which is
about 1.2 x 10-6 cm or 1.2 x 10-8 m or 12 nm. Consequently,
the distance between each charge within the single layer of

Quantal Rather than Molecular Pathways Current Medicinal Chemistry, 2010 Vol. 17, No. 27 3095
charges on the cell surface is within the same order of mag-
nitude and coefficient as the thickness of the cell membrane
(about 10 nm).
This similarity is not spurious. The classical electric force
between the charges is F=(qaqb)/(r2 4pi e)), where qa and qb
are the two unit charges, r is the distance and e is permittivity
constant. The force at the 12 nm distance between charges is
(1.61 x 10-19 As)2 /[(1.1 x 10-8 m)2 x 12.56 x 8.85 x 10-12
C2/Nm2] or 1.8 x 10-12 N. This pN (picoNewton) value is
within the range observed for intermolecular forces [6].
However energy is force over distance. The application of
this force of 1.8 x 10-12 N over a distance of 1.2 x 10-8 m is
2.2 x 10-20 J. From this perspective the kinetic energy associ-
ated with each action potential on charges is simply the con-
servation of the potential energy between the charges.
The energy can be derived by the product of the voltage
and current dipole divided by velocity of the electrons. As-
suming a current dipole of 20 fA m or 2 x 10-14 A m [7] the
velocity of a unit charge of 1.6 x 10-19 A s would be about 1
x 105 m/s. This value is similar to the estimated velocity re-
ported by Cosic [8] for free electrons to move along the
DNA backbone. Consequently the product of the voltage of
10-1 V and the equivalent dipole moment of 2 x 10-14 A m
divided by 1 x 105 m/s would about 2 x 10-20 J, the critical
quantal unit.
This solution is complimented by the relationship to ca-
pacitance. Energy (J) is equal to the square of the dipole
moment divided by the capacitance [(A m)2]/[(A2s4)/kg m2)]
and then multiplied by the square of the duration (s2). The
solution of 10-28 A2m2/10-14 F/um2 is 10-14 J multiplied by s2.
To obtain 10-20 J the value for s must be 10-3 sec (1 msec),
the typical range of the duration of the action potential. Con-
sequently the temporal duration of the process involved with
the basic mediation of digital information through brain
space is convergent with the quantum of 10-20 J.
The continuity of the 10-20 J is evident during the in-
tersynaptic transformation of an action potential to the re-
lease of chemical species from vesicles. The current Ii asso-
ciated with a single post-synaptic potential with a current
dipole moment (Q) of 20 x 10-15 A m s and the length con-
stant of a dendrite [7] of about 0.2 mm (2 x 10-4 m) would be
the quotient of 1 x 10-10 A. With 1.6 x 10-19 A s per charge,
this means there are 109 charges involved over 1 sec or 106
charges within 1 msec for 1 channel or the requirement of
between 100 and 1,000 ion channels over periods of 1 to 10
msec. The product of voltage, current, and time is energy.
Either the product of 10-6 V, 10 -10 A and 10-4 s (the order of
magnitude of intersynaptic diffusion time for classical neuro-
transmitters) or the product of 10-7 V, 10-10 A and 10-3 s re-
sults in a value of 10-20 J.
The hypothesis of serial quanta, whose temporal patterns
define the information within the biosystem, would require
equivalent values within the next step in the sequence: recep-
tors. Ionotropic glutamate receptors, that mediate most of the
fast excitatory neurotransmission of the brain, manifest as
bilobular proteins with a cleft between the two lobes. Full
agonists result in an interlobe hydrogen bond between
Glu402 and Thr686 of the protein [9] whereas antagonists do
not produce this conformation.
The hinge motion subsequent to the sequestering of the
agonist (glutamate binding) is associated with an energy
change estimated to be 8.8 kJ/mole [9]. This is equivalent to
about 1.5 x 10-20 J per molecule. Glutamate neurons often
display a resting membrane potential closer to threshold, a
feature that encourages burst-firing. Consequently, the slight
difference in coefficient would reflect the proportional re-
duction in absolute change in voltage associated with these
action potentials.
2.2. Metabolic Conservation
If the source of the energy within the brain is primarily
derived from glucose, then the 10-20 J unit should be re-
flected in this metabolism. With an average glucose oxida-
tion of 35 microMoles/min/g of tissue [10] a brain of 1.35 kg
would use .35 x 10-6 M/min/g x 1.66 x 10-2 min/s x 1.35 x
103 g or .78 x 10-5 M/s. If one mole of glucose produces 2.87
x 106 J, then this value multiplied by .78 x 10-5 M/s indicates
the whole brain volume would employ on average about 22
J/s or generate 22 Watts. The efficiency ratio of glucose me-
tabolism would only affect the coefficient.
The energy density per cc of tissue, assuming 1 gm=1 cc
because the specific gravity of brain tissue approaches unity,
would be 1.47 x 10-2 J/cc or J/g per sec. With the area of the
cell membrane being 3.14 x 10-6 cm2 for a cell with a width
of 10 um and a thickness of 1 x 10-6 cm (10 nm) the volume
is 3.14 x 10-12 cc. The potential distribution of energy from
glucose metabolism within this shell would be 3.14 x 10-12 cc
times 1.47 J/cc or 4.61 x 10-14 J.
Because the energy involved with the distances between
charges that contribute to a membrane potential of 70 mV is
1.12 x 10-20 J, this means that the membrane could "store" or
dynamically transport approximately 4.61 x 10-14 J/1.12 x 10-
20 J or 4 x 106 charged units. This is the order of magnitude
of the numbers of ions required to maintain the resting mem-
brane potential. The congruence of values suggests that the
energy is conserved even within metabolic domains and that
the "charge separation" energy may not be simply "electro-
static" but instead based on glucose derived thermal energy
or some shared source of variance creating both.
The validity of these calculations and concept is sug-
gested by the relationship between energy density within the
cell and the numbers of functional molecules that it contains.
With a cell volume of 5.23 x 10-10 cc (10 um diameter) and
20 J/1300 cc of brain volume, the average energy per cell
volume would be about 10-11 J. If each molecule is carrying
successive quanta of 10-20 J then about 109 molecules could
be maintained. This is equivalent to the numbers of su-
praBoltzman-energy requiring enzymes and nucleotides
within cells, including the neuron [11]. This number of
molecules within the aqueous environment per cell volume
would be equivalent to an average concentration of between
10 to 100 mM.
2.3. Cell-Cell Adhesion Forces
Cells are constantly exposed to minute time-varying me-
chanical forces evoked by intrinsic contractions or by a vari-
ety of environmental stimuli. The conversion of physical
signals, such as contractile forces or mechanical perturba-

3096 Current Medicinal Chemistry, 2010 Vol. 17, No. 27 M.A. Persinger
tions, into events mediated by chemical signalling is a fun-
damental cellular process. The interfaces, focal adhesions,
occur within the cell-extracelluar matrix.
According to Bershadsky [12], the stress forces exerted
by cells at focal adhesions, as obtained by several methods,
average about 5 x 10-9 N/microm2. The multiplication of the
volume (um3) in which this pressure occurs results in energy.
If the quantum of 10-20 J is assumed, then the volume re-
quired for this force would be .42 x 10-11 microm3, the cube-
root of which is .16 x 10-3 microm or .16 nm. This width is
within the range of the distance of atomic bonds, particularly
covalent bonds (0.15 nm) rather than ionic (.25 nm), hydro-
gen (.30 nm) or van der Waal (.35 nm) forms. This solution
suggests the importance of the 10-20 J quantum as a funda-
mental unit of interaction not only within cells but between
cells.
3. EXPERIMENTAL EXAMPLES OF 10-20 J
TRANSFORMATIONS
If there are essential quanta of transfer of information in
biochemical reactions, the solutions should be evident in any
process for which sufficient details are available. An exam-
ple from three classes of processes demonstrates the validity
of the concept. The first involves the authors research with
measurement of quantum emission from cells in culture. The
second involves the transfer of quanta, as chemical reactions,
in serial steps of phosphorylation within general molecular
signalling pathways. The third involves the transfer of a
quantum, as light, in chromophores.
3.1. Direct Measurements of Photon Emissions From Cell
Cultures
For the last two years we [13] have been obtaining meas-
urements from photomultiplier tubes (PMT) to discern the
intrinsic activity of cells in culture. Cell types have included
BCL-16 (mouse melanoma), HEK (Human Embyronic Kid-
ney), HSG (Human Salivary Gland), SK-Mel (Human Mela-
noma), THP and U937 (monocytic-like leukaemia) and
HELA. In more than 100 trials, cells were removed from
standardized incubation (37 deg C) and maintained for 12 hrs
in a darkened room at room temperature (20 deg C). The
changes in energy emission are conspicuous with peaks over
several hours corresponding to alterations in membrane po-
tentials. PMT measurements from media only displayed no
fluctuations.
The plastic dishes containing the cells were placed over
the aperture of the photomultiplier tube and the quantified
emissions were recorded as changes in mV three times per
sec by laptap computers. The specific values were extrapola-
tions from calibration by LEDs at fixed distances and veri-
fied with sensitive luxmeters. Staining with acridine orange
and ethidium bromide after removal from the experimental
setting demonstrated the cell membranes had remained func-
tional for eight hours after removal from incubation. After
24-hr diminished selective permeability of the membrane
was clearly evident by the density of ethidium bromide. Try-
pan blue showed a small proportion of dead cells.
The most consistent and conspicuous observation has
been the occurrence of about a 2 x 10-20 J functional unit
from each cell. Within our experimental paradigm 1 unit
fluctuation of the PMT metric was equivalent to 5.4 x 10-11
W/m2. With a PMT aperture radius of 1 cm, the total energy
is about 17 x 10-15 J/s per dish of cells and with 5 x 105
cells/dish this is equivalent to between 3 and 4 x 10-20
J/cell/s. Fourier and spectral analyses of either 2-hr or 12-hr
trains of data (3 samples/s) revealed the strongest peak to be
around 1 Hz. Even with an excessive estimate of 100% (fac-
tor of 2) opacity and loss the energy fluctuations per cell
would be in the order of 2 x 10-20 J. The coefficient either
doubled or was reduced by half when the numbers of cells
were changed by that factor.
3.2. Phosphorylation and Specific Reaction Steps
Posttranslational modification of proteins by phosphory-
lation is a ubiquitous mechanism by which many cellular
functions are controlled. Miranda et al. [14] reported that the
energy difference between the phosphorylated and unphos-
phorylated subunits of phenylalanine hydroxylase was 11
kJ/mole or 1.8 x 10-20 J per site. They also showed discrete
quanta in the change in energies for charge-charge interac-
tions between the unphosphorylated and phosphorylated sites
along the residual numbers (amino acid sequence). It is rele-
vant that breaking of second shell hydrogen bonds, an essen-
tial step in the structural diffusion of protons (proton conduc-
tion) in water, is 1.8 x 10-20 J or 10.9 kJ/mol [15].
As predicted, thermodynamic parameters for the binding
of peptides to the Grb (growth receptor bound) 7-SH2 do-
main was also equivalent to 2 x 10-20 J per site according to
Spuches et al. [16]. The Grb7 family has been argued to fa-
cilitate more specialized signalling pathways. It is expressed
particularly in the liver, kidney, and gonads [17] and is co-
overexpressed with erbB2 in about 25% of all breast cancers
[18]. The enhanced metabolism through electron chains con-
verges with the 1.8 x 10-20 J "quantum" obtained from 1/2 the
product of the mass of an electron (9.1 x 10-31 kg) and the
square of average of the Cosic [8] velocity of 2 x 105 m/s for
electrons moving along proteins.
3.3. Green Fluorescent Protein
Bioluminescence is light produced by a chemical reaction
that occurs in an organism. Dinoflagellates are unicellar pro-
tists, primarily plankton. Zooxanthallae, the most common
symbiotic dinoflagellates, are found in sponges, flatworms
and jellyfish. Upon binding with calcium the green fluores-
cent protein (GFP) responsible for this phenomenon releases
a quantum of energy perceived as blue light. The blue light is
absorbed by a green fluorescent protein that in turn emits a
green light. A classic example is the absorption of 395 nm
and the release of 508 nm.
The energy difference, or quantal display, for these two
wavelengths if one assumed 3 x 108 m/s for the velocity of
light would be in the order of 10-18 J. However the velocity
of light in water varies as a function of wavelength [19], with
values of 2.147 x 108 m/s for 370 nm to 2.206 x 108 m/s at
520 nm. The difference in energy (J=Planck's constant mul-
tiplied by frequency) would require accommodating the dif-
ferent velocities in water when obtaining the specific fre-
quencies. For 395 nm the value is 3.6212 x 10-19 J and for

Quantal Rather than Molecular Pathways Current Medicinal Chemistry, 2010 Vol. 17, No. 27 3097
508 nm the value is 2.8720 x 10-19 J. The net energy release
per reaction would be 7.4 x 10-20 J. This would be sufficient
for about 2 to 3 action potential equivalents. According to
Meech [20] this is the number of low-threshold calcium
spikes per sec displayed by the prototypical jellyfish Algan-
tha digitale.
4. BIOLOGICAL SIGNIFICANCE OF A QUANTAL
MEDIATOR
4.1. The Potential Evolutionary Source
The source of the approximately 2 x 10-20 J quantum may
emerge from the narrow range of temperature within which
life exists. According to Wien's law, the wavelength ((0.29
cm-deg)/ T) at 310 deg K (37 deg C) would be 9.35 x 10-6 m
(9.35 micrometers) which is conspicuously similar to the
width of the average cell. This wavelength is 3.2 x 1013 Hz.
When this frequency (1/s) is multiplied by Planck's constant,
h (6.63 x 10-34 J), to obtain a classical energy value, the
quantum of energy is 2.2 x 10-20 J.
4.2. Implications for Storage of Energy and Numbers of
Action Potentials
The energy stored within a volume from a magnetic field
is (B2/u) multiplied by the volume where B is the strength of
the field in Tesla, and u (mu) is the magnetic permeabil-
ity=4pi x 10-7 N/A2. For the volume (4/3 pi r3) of soma with
a diameter of 10 micrometers, the volume is 5.24 x 10-16 m3.
Consequently within the earth's static magnetic field of
50,000 nT or 50 microT (0.5 gauss), the energy stored within
the magnetic field volume is (25 x 10-10 T2)/(25 x 10-7 N/A2)
multiplied by 5.23 x 10-16 m3 which equals 5.2 x 10-19 J.
With 2.0 x 10-20 J per action potential this allows for 32
action potentials per sec which is within the average range of
pulses over protracted time. The increase in magnetic poten-
tial energy in the cell volume increases non-linearly such that
a small neuron (5 microm wide) would average around 4
spikes/s while a larger neuron (50 microm) could exceed
1000. Consequently the volume of the soma could reflect the
magnetic energy that is sufficient to set limits on the number
of action potentials per second.
5. SUMMARY AND IMPLICATIONS
That information could be carried by quantized amounts
of energy within a narrow range of energy suggests the exis-
tence of an intrinsic organization whose identification and
isolation would allow a parsimonious understanding of what
is now approaching an overwhelming complexity of molecu-
lar pathways. The existence of a very narrow energy range
within which information is distributed is not unique. Many
computer systems operate within the -5 to +5 V range. Val-
ues above or below this critical window are either destruc-
tive, interfering, or not effective.
If the critical component is the serial quanta of informa-
tion within the space-time constraints of the cell, then the
emphasis upon identifying "the" molecular pathways for
normal conditions and for the treatment of disease may be
less productive than anticipated. The many, apparent "paral-
lel" systems and the extremely intricate pathways with mul-
tiple feedbacks, feed-forwards, and lateral effects, would be
epiphenomenal. The emergence and maintenance of these
myriad pathways would emphasize the biological and func-
tional importance of having a reservoir "vehicles" available
to insure the transport of biological quanta. It would be
equivalent to transporting a person across a country. No mat-
ter which vehicle is employed, the individual being carried is
the same person at the destination.
Secondly, every particle (mass) within the brain and
other organs is also associated with a wave propagating
through space. In other words for ever chemical sequence
there should be an equivalent wave-sequence. As empha-
sized by de Broglie [21], matter waves are phase waves of
the matter field associated with motions of quanta as they
spread over the whole of space. An aggregate of particles
that compose each organ should exhibit a macroscopic wave
function operating within a collective mode similar to the
propagation of wave of the matter field.
This assumption indicates that the information involved
with the maintenance of cell function, particularly within the
brain, can be strategically affected or "treated" through either
particulate matter (chemical sequences) or the equivalent
wave functions (electromagnetic patterns) that reflect the
organization of this information in space and time, respec-
tively. New and yet to be developed technologies that focus
upon directly influencing the temporal pattern of biological
quantum within the range of 10-20 J could be a more direct
and efficient means of changing cell function and hence
treating the physicochemical bases of diseases rather than
attempting to isolate and to map the innumerable and differ-
ent molecular signalling pathways that differ not only be-
tween cell lines but between types of the approximately 10
trillion cells within the body.
The approach of modern neural science [22] has implic-
itly assumed that neuronal resting potentials can be ex-
plained without the requirement for quantum mechanics.
From this perspective the resting potential and the phenom-
ena dependent upon it can be accommodated by the concrete
application of the Nernst equation and Ohm’s law in the
form of the Goldman-Hodgkin-Katz equation. When the
membrane potential changes the energy associated with each
ion changes accordingly.
However the third consideration derived from the con-
cepts presented in this paper is that the intrinsic functions of
all biosystems can be related to fundamental quantum prop-
erties, as originally postulated by Schrodinger [2] and Bohr
[3]. If the energetic units by which information is generated
and maintained within living systems are reflections or even
identities with the essence that defines all of space and the
forces within it, then the paradigms by which we view and
understand "life" and its medicinal chemical treatment may
require some modification.
ACKNOWLEDGEMENTS
Thanks to Viger Persinger and Mathew Hunter for con-
structive criticisms and technical assistance.

3098 Current Medicinal Chemistry, 2010 Vol. 17, No. 27 M.A. Persinger
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Received: March 29, 20 10 Revised: J une 29, 2010 Accepted: June 30, 2010