The imidazole ring of proline allows a polypeptide folding dynamics by H- bonds breakdown sliding for a vectorial exergonic hydrophilic to an endergonic hydrophobic configuration for Hb and active site functions

Abstract

Prigogine proposed a coupling between larger sources of enthalpy to allow an open system to operate life. The sun flow of energy is coupled to water cluster thermogenic breakdown of H-bonds to vapor. The position of proline in a polypeptide chain allows sliding between segments, in the tertiary folding structure response to electrostatic attractions, could differentiate positive vs negative domains. Thus, bypass the microscopic reversibility principle, illustrated as a single door, vectorial kinetic only made possible by the jokingly Maxwell proposed operator demons. The physiological function of Hb oxygenation by pO2 shows a microscopic thermogenesis biological vector, functioning by the enthalpy potential of the large mass action of surrounding air and releasing entropy. The mechanism shows the H-bonds breakdown required for changes in the structure-function levels by the proline mediated folding. The tense (T) to relax (R) forms shows vectorial microscopic dynamics, during Hb oxygenation. Thus involves a sliding by H-bonds breakdown, distancing between subunits and. Thus, open a larger entrance to a fully hydrated Mg 2+ to coordinate amphoteric and negative R groups characterizable to a hydrophilic site. The transition of R to T allows positive R groups to bind 2,3-DPG 5-to form deoxyHb. Thus, a microscopic smaller entrance by decreasing its opening size does not allow entrance of the fully hydrated Mg 2+ , but allow the exit of nitric oxide (NO) and a poorly hydrated Mg 2+ , denominated nascent. This one acts for competitive hydration sieving on the shells of Na + , which in terms take water from the K + shell, potentiating a K + /Na +-translocation operating the electrogenic transmembrane potential. The deoxygenation in the reverse transition of R to T binds NO, protecting against a premature decrease of the chromosome's telomeres size by stressing factors such as depression, anxiety and physic traumatisms, over endothelial cells delaying premature senescence. The arginine metabolism produces NO, dilating blood vessels, improving the circulatory systems and the muscular recovery-development. In vascular niches, endothelial cells of blood vessels produce NO, which activates the Notch signaling pathway of neighboring cancer stem cells, thus regulating their self-replication. A diet rich in arginine by producing a high sustainable level of NO may prevent the resistance to treatment by the consolidation of large vascular masses. The H-bonds donor potential by their breakdown leads to randomness (or entropy) decreasing the kinetic energy of solvation, scaling down the polarity on the thermogenic dissipation of oxy vs deoxyHb and choroid plexus epithelium on plasma generation of cerebrospinal fluid (CSF). The enthalpy of photosynthesis-metabolism releases CO2, whereas the water cluster mediated thermostatic function releases vapor. In both systems, the entropy release maintains a high potential of enthalpy. Hence, overcomes the thermic and electric noises by an irreversible dissipative kinetics, facilitating a clear development of a meditative level of reasoning and learning. Thus, the brain acquires an autonomous function, beyond behavioral genetic conditioning.

Full text

1
The imidazole ring of proline allows a polypeptide folding dynamics by H-
bonds breakdown sliding for a vectorial exergonic hydrophilic to an
endergonic hydrophobic configuration for Hb and active site functions
Dr. Alfred Bennun
Full Professor Emeritus of Biochemistry
Rutgers University
Abstract
Prigogine proposed a coupling between larger sources of enthalpy to allow an open system to operate life. The
sun flow of energy is coupled to water cluster thermogenic breakdown of H-bonds to vapor. The position of
proline in a polypeptide chain allows sliding between segments, in the tertiary folding structure response to
electrostatic attractions, could differentiate positive vs negative domains. Thus, bypass the microscopic
reversibility principle, illustrated as a single door, vectorial kinetic only made possible by the jokingly Maxwell
proposed operator demons. The physiological function of Hb oxygenation by pO2 shows a microscopic
thermogenesis biological vector, functioning by the enthalpy potential of the large mass action of surrounding air
and releasing entropy. The mechanism shows the H-bonds breakdown required for changes in the structure-
function levels by the proline mediated folding. The tense (T) to relax (R) forms shows vectorial microscopic
dynamics, during Hb oxygenation. Thus involves a sliding by H-bonds breakdown, distancing between subunits
 and . Thus, open a larger entrance to a fully hydrated Mg2+ to coordinate amphoteric and negative R
groups characterizable to a hydrophilic site. The transition of R to T allows positive R groups to bind 2,3-DPG5-
to form deoxyHb. Thus, a microscopic smaller entrance by decreasing its opening size does not allow entrance
of the fully hydrated Mg2+, but allow the exit of nitric oxide (NO) and a poorly hydrated Mg2+, denominated
nascent. This one acts for competitive hydration sieving on the shells of Na+, which in terms take water from the
K+ shell, potentiating a K+/Na+-translocation operating the electrogenic transmembrane potential. The
deoxygenation in the reverse transition of R to T binds NO, protecting against a premature decrease of the
chromosome’s telomeres size by stressing factors such as depression, anxiety and physic traumatisms, over
endothelial cells delaying premature senescence. The arginine metabolism produces NO, dilating blood vessels,
improving the circulatory systems and the muscular recovery-development. In vascular niches, endothelial cells
of blood vessels produce NO, which activates the Notch signaling pathway of neighboring cancer stem cells,
thus regulating their self-replication. A diet rich in arginine by producing a high sustainable level of NO may
prevent the resistance to treatment by the consolidation of large vascular masses. The H-bonds donor potential
by their breakdown leads to randomness (or entropy) decreasing the kinetic energy of solvation, scaling down the
polarity on the thermogenic dissipation of oxy vs deoxyHb and choroid plexus epithelium on plasma generation
of cerebrospinal fluid (CSF). The enthalpy of photosynthesis-metabolism releases CO2, whereas the water cluster
mediated thermostatic function releases vapor. In both systems, the entropy release maintains a high potential of
enthalpy. Hence, overcomes the thermic and electric noises by an irreversible dissipative kinetics, facilitating a
clear development of a meditative level of reasoning and learning. Thus, the brain acquires an autonomous
function, beyond behavioral genetic conditioning.
Introduction
The chloroplast’s studies showing the vector
kinetic of the ATP synthase-ATPase was in
apparent contradiction with the principle of
microscopic reversibility. The impossibility to
differentiate between hot- and cold-molecules
allowed a humorous description by Maxwell that the
operators of a single door, capable of doing so,
should be called demons.
Figuratively, the principle describes that a
single microscopic door allows transit in both
senses, allowing only a closed thermodynamic
system, which only allows changes by mass-action
equilibrium. However, an irreversible open system
do have vectorial kinetic as long that enthalpy is
totally dissipated.

2
Hence, to evade that incompatibility [
1
], it is
possible to assume two inversely linked doors,
mutually exclusive, one open to be when the other
is closed. The conformational changes described are
operating when one domain is hydrophilic and the
other turns to become hydrophobic.
Vectorial kinetics is conferred by proline-
dependent polypeptide folding dynamics. The H-
bonds could be regarded as doors, when open
attracts water cluster to the segment containing
negative R groups capable to coordinate  (first
door).
This hydrophilic configuration has to be
mutually exclusive by H-bonds breakdown (second
door) to reconfigure a hydrophobic structure of
positive R groups to attract negatively charged
molecules like  and . However, the
endergonic product: cAMP, which could not be
liberated from a hydrophobic close environment,
which allows water exclusion for vectorial decrease
in energy of cyclization. However, Mg-cAMP is
released by the large mass action of water clusters
and the increase in free . Turnover requires
the mass-action of water cluster for additional H-
bond breakdown, reconfiguring the obligatory Mg
site characterizing the hydrophilic state.
These are transitions thermodynamically
coupled between an exergonic reaction couples to
drive the endergonic, sliding event by the H-bonds
breaking of the binding folding dissipative heat
release.
The directionality would be given by mutual
exclusion and this complementarity would be the
conformational change of the protein, dependent
on a breakdown of a small ratio of H-bonds of the
total potential of the water cluster. A subsequent
event depends on the exergonic uphill event of H-
bond breakdown to recreate the hydrophilic domain
(3th door). However, this step has the large
contribution to the enthalpy of the system by a
natural coupling to the high H-bond mass action of
water clusters at molar level. The system operates
with the remaining H-bonds within the water
cluster. This is rather not detectable since at the test
tube reactants and products are at molar level.
However, the water cluster involves the solvation
energy of encompassing saturation surroundings [
2
]
[
3
] [
4
] [
5
].
Experimentally the solvation tendency was
measured on the activity shown by the heat
activated-ATPase, determined from its maximal
value assayed as basal with glycerol addition at 0%
only in the presence of water clusters. The curve
obtained by decreasing enzyme activity to zero is
reached by adding glycerol to reach 8%
concentration into the mixture.
A Lineweaver plot allowed the determination
of a cooperativity number of 16 that divided by two,
a value for the microscopic energy of solvation. The
presence of two active sites revealed that each one
was structured by the binding of water at 8
solvation sites. Therefore, the basal condition
showed that glycerol was a competitive antagonist
to H-bond breakdown.
The number of 2-, 3- and 5-coordinated water
molecules produced from broken tetrahedral
structures increase upon heating [
6
]. Temperature
and shearing can break down a large number of H-
bonds within a network. At low temperatures 50%
of water molecules are included within clusters.
With increasing cluster size the oxygen to
oxygen distance is found to decrease, which is
attributed to so-called cooperative many-body
interactions: due to a change in charge distribution.
The H-acceptor molecule becomes a better H-
donor molecule with each expansion of the water
assembly. Many isomeric forms seem to exist for
the hexamer 󰇛󰇜 from ring, book, bag, cage, to
prism shape with nearly identical energy. Two cage-
like isomers exist for heptamers 󰇛󰇜 and
octamers 󰇛󰇜.
The imidazole ring of proline role in
polypeptide dynamics
The H-bond dynamics on folding allows the
peptide bond a resonance stabilized polar and
planar structures. Two parallel -pleated sheets with
an intervening strand of  helix domains bends on
the surface of globular proteins. This structure
offers little steric hindrance to a modification in the
direction of the polypeptide chain.
The imidazole ring, a five-membered ring of
proline, allows a second residue to manifest a
reverse turn.
Constructing mutual exclusion domains
through H-bonds turnover allows the interaction
between distant regions of a polypeptide chain. The
hydrophobic effect drives protein folding in about

3
 to   to rotate around the    and
   bonds of the polypeptide backbone.
Figure 1: Dynamics of isomer cis of proline in
configuration allowing sliding between two
domains helix-turn-helix changing the
correspondence between a hydrophobic vs
hydrophilic site.
Required to bend, twists and folds the
polypeptide sequence at the tertiary structure level,
by producing differential configurations by
hydrophilic associations of cations 󰇛  
 󰇜 and hydrophobic for anions 󰇛  
   󰇜.
Hemoglobin and O2/Mg2+ control of a
membrane action potential
The crystallography x-ray analysis by Max
Perutz [
7
] was able to determine the quaternary
structure of oxyHb, without characterization of the
 role for a hydrophilic site.
The oxyHb has a topology of two hydrophilic
interphase  and  that coordinate one
 each. In deoxyHb the topology is
restructured by the tetramer subunits, lining
positivity-charged R groups of amino acids and His
 143 that turns around into the central pocket to
bind  . A decrease in pH favors the
protonated forms for formation of deoxyHb.
Hence, the oxyHb contains two interphases to
coordinate  into hydrophilic domains, which
are mutually exclusive with a single 
-
dependent domain included in the tetramer
structure of deoxyHb [
8
] [
9
] [
10
] [
11
] [
12
] [
13
].
The conformational irreversible change
involved two Mg2+ chelating dynamics interfaces in
the Hb tetramer with a His R groups at the interface
of  chains of Hb, an a second symmetric
chelating site at the  interface for each .
The conformational change by the release of 
and  at tissue level became irreversible
because the amphoteric R group His 143 move
from coordinating Mg2+ at oxyHb to integrate the
deoxyHb to conform within the positive R groups
that form a single binding center for   at
the deoxyHb.
At the deoxyHb a vectorial by kinetic by the
sieving effect at the subunit by the R group of
Pro 44 sliding between  His 97 and  Thr 41 to
block now the entrance of the larger fully hydrated
 into the interface of  and  chains, which
now only allows the exit of the smaller incompletely
hydrated: nascent . The neutral soluble in fat
and water NO enters attracted by the positive R
groups, holding  .
The absence of guanylate cyclase activity at the
human red cells shows its capability to be a carrier
of cGMP by its uptake from extracellular fluids.
The erythrocyte uptake of cAMP and cGMP
allow their signaling to participate in the regulation
of intracellular process, without in situ formation
because could be delivered by blood [
14
].
At tissue level the erythrocyte, at low  the
Hb protein release of  jointly with the
breakdown of 2 coordinated  ( or )
atoms, involved the existent of vectorial kinetic by
the movement of the pyrrole R group of Pro  44,
allowing the tertiary structure for sliding of the
 positions in amino acids polypeptide
subunits.
Thus opening in the T-->R transition for
uptake and coordination of Mg2+ and closing in the
R-->T transition for releasing and preventing the
coming back of  the system shows vectorial
kinetic. Thus, evading the principle of microscopic
reversibility since the event could be characterized
by over two linked conformational changes, acting
synchronized in inverse relationship, one open and
the other closed hereby described as mutual domain
exclusion.

4
Figure 2: The four Heme oxygenation sites correspond to two dimer interfaces:

and

.
The
negative R groups force the release of NO when 2Mg2+ coordinate and 4O2 occupy the 4 heme to form the hydrophilic oxyHb. A
relax (R) form of oxyHb has a pKa=6.2 acting as a carrier for O2 and Mg2+ to be release at tissue level. The action results in the
hydrophobic tense (T) form of deoxyHb pKa=8.2. The in between H-bond breakdown allows an irreversible kinetic step, between
both forms of Hb, because are mutually exclusive.
The  pressure between lung and tissue level
becomes the physiological/biological driving for an
open system function relates to cycle of , but
since the turnover itself comprises conformation
changes is also coupled to the H-bond breaking out,
releasing energy and the large mass action of water
cluster 󰇛󰇜 to reconstruct the solvation state.
The H-bonds decreases  and the single molecule
of water formed without H-bond as vapor. Thus,
both sources of energy are dissipative functions
with irreversible kinetic in the absence of solar
energy.
Peptide bonds are rigid and fixed in a plane in
where two -carbons, 3.6  apart, rotate by angles
 (fi) and  (psi). The tertiary structure in the 2
and 2 polypeptide chains of Hb bends, twists and
folds over and back upon imidazole R-groups. With
pKa of 6.5 that at about pH 6 shows two NH
bonds that share in a resonance a positive charge.
Hence, the hydrophobic state form of the protein
by an  induce conformational changes 
dimer to rotate 15o around of other dimer .
The two His  and  143 during
oxygenation are changed in relative position by the

5
quaternary restructuring topology and move to the
interphase  and  to participate in the
disruption of the 2,3-DPG binding site. Hence, the
oxyHb contains two ions at the interphases: Mg2+-
dependent hydrophilic domain, which is mutually
exclusive by rotating His  143 into binding with
2,3-DPG. This R group, the amphoteric or
zwitterionic form (can react both as an acid and as a
base) changes hydrophilic state to be included in the
positive R group domain of  , within the
tetramer structure of positive deoxyHb.
The two dimer interfaces:  and  link
by two 󰇛󰇜 the dynamics of
conformational change to an hydrophilic state of
the protein, by chelating [
15
] the R groups His  92,
Cys  93 and Asp  94, could attract sequentially
the iron in the 4 hemes by His  92, moving to
coordinate  and coordinate to His  87. The
4 irons within the 4 Hemes could move to the
outside surface to interact with the distal His  63,
increasing Hb affinity for the ligands by forming an
H-bond with .
The publications at Rutgers [
16
] showed
conformational allosteric changes, were kinetically
depend of hydrophilic configuration to form a
coordinative center for  (or ), operating
the dynamics of R groups response to oxygenation.
The His  87 moves by  coordination
to interact with the oxy Heme .
Deoxygenation allows His  143 to be
released from  to participate in the  
stability.
Thus, shows that the mutual exclusion
between binding  or   has synchronized
the motion of R groups responding to oxygenation
function.
The importance of this contribution was to
show protein dynamics in reference to pressure of
 mass action in the orientation of hydrophilic R
groups (His, Cys, Asp).
The binding of   to charged positive R
groups lead to hydrophobic state of the protein,
with the energy potential in the protein structure in
the direction of the spontaneous exergonic
dissipative state and therefore the system becomes a
potential dissipative thermodynamic path, between
hydrophilic oxyHb and hydrophobic deoxyHb.
The dissipative potential functions from the
greater atmospheric  pressure to the lower one at
the tissue level, became self-organized by 
sequential coordinative from negative residues and
the amphoteric histidine. Thus,  pressure creates
maximizes potential by Mg2+ saturation through bi-,
tetra-, hexa-dentate stages, and steadily releases
along the differential axis of tissue consumption of
 delimited by lower and lower pH (the vertical
human posture favors oxygenation of its brain, over
that its lower extremities, absent at the quadruple
posture of other mammalian.
The model explains sigmoidal binding
properties (i.e. positive cooperativity) by the
progressive binding by 󰇟󰇛󰇜󰇠 from two
to fourth to six coordinative states with the
corresponding number of R groups.
An open system magnifies the function of the
mass action of substrate concentration because the
product is in a dissipative state and therefore could
acquire a lower concentration than predicted from
kinetic equilibrium.
Accordingly, at the brain membrane potential
transmission of electric signal are potentiated well
above that of thermic noises. Thus, because
adrenaline could not cross the blood-brain barrier
(BBB), the body became restricted to signal stress
feedback, capable to turn-off the hypothalamic-
pituitary-adrenal (HTPA) axis to persist in
exhaustion of metabolic reserves.
This system allows the human brain to be
conditioned by achievement related to the euphoric
sense of an athletic successful performance, even at
the cost of stressful events. The mechanism may
involve the conversion of dopamine to
noradrenaline (NA) by dopamine β-
monooxygenase, which occurs predominantly inside
neurotransmitter vesicles.
Most vertebrate species devote between 2%
and 8% of basal metabolism to the brain. In
primates, however, the percentage is much higher in
humans it raises to 20–25%, a person uses about
320 calories only to think. Thus, this exceptional
energy expenditure leads to autonomous
thermogenesis, involved in the daily turnover
consuming 450ml of cerebrospinal fluid (CSF), to
be released as a 5% of vapor in exhaled air.
The vomeronasal organ (VNO) [
17
] [
18
] in the
oral cavity contains the cell bodies of sensory
neurons which have receptors that detect specific
non-volatile (liquid) organic compounds which are
conveyed to them from the saliva, environment, etc.

6
Hb transport of nitric oxide
The enzyme nitric oxide (NO) synthase
catalyzes from arginine the products citrulline and
NO. This one is a strongly reactive radical by having
an unpaired electron, solubility in water and lipids,
which allows crossing biological membranes.
Endothelial cells at the blood vessels surround
smooth muscles, which do not have sarcomeres
(involuntary non-striated muscle). Muscarinic
receptors to acetyl choline (ACh) distend muscle.
The endothelial release of  binds to calmodulin
activating the enzymes hemoxygenase: HO-1
(spleen and liver) for NO and HO-2 (brain) for CO
from Heme group of Hb, and a third system CSE
producing H2S.
Nitric oxide synthases (NOSs) synthesize the
metastable free radical NO. Three isoforms are
known for the NOS enzyme: endothelial (eNOS),
neuronal (nNOS), and inducible (iNOS) - each with
separate functions.
NO and CO integrate to activate the cellular
smooth muscle activating guanylate cyclase (sGC),
generating from GTP the product cGMP. The latter
by bridging actin and myosin relaxing muscle and
H2S, activating the K+ discharge through the K+
channel, and dilatation of blood vessels.
At low concentrations of the 3 gases
contribute to control blood pressure, favor the
release of other transmitters and hormones,
protecting cells from the oxidative stress. At the
brain stimulates learning and cognition. NO
differentiates from other transmitters usually
enclosed in vesicles and liberated at synapsis like
acetylcholine, dopamine and glutamate. NO could
diffuse to a distance of 300, reaching
simultaneously    synapses. Thus, activates in
a retrogression manner, the presynaptic neuron.
Thus, the process could prolong for many hours the
liberation of neurotransmitters by the neurons to
potentiate a learning state.
The broad spectrum of NO release of other
transmitters in the nervous system, dilates blood
vessels in the cardiocirculatory system, protects
against oxidizing agents in somatic cells, participates
in learning and memory processes in the brain, in
the lungs relaxes the respiratory muscles and relaxes
the digestive tract and produces erections.
The NO protector effect is expressed along the
body and it is considered aggressive at large
concentration, it has an odd electron that makes it
very reactive and volatile.
The macrophages of the immunity system and
the astrocytes microglia, producing myelin at the
brain axons has been endowed with a toxic barrier
indistinctly acting against all microorganisms,
parasites and tumor cells. Hence, is a nonspecific
inborn, constitutive and protective defense that
could be increased by diet, including arginine.
Consequently, adds to the specific antigenic
action by the reaction produces by microorganisms
generating disease, which leads the immunity system
to produce the corresponding recognizing anti-
bodies, which can be reinforced by vaccines.
The NO could react with peroxide water
󰇛󰇜 to produce peroxynitrite 󰇛󰇜.
NO in excess could damage cells and at the
neuromuscular synapsis activates cAMP production,
potentiating the cAMP response element binding
protein (CREB). Also, inhibits the cAMP
destruction by phosphodiesterase prolonging its
time action, favoring a neuronal circuit plasticity
state.
Dietary nitrate as source of NO green, leafy
vegetables is concentrated by about 10-fold in saliva
and reduced to nitrite in the surface of the tongue
by a biofilm of anaerobic bacteria [
19
]. In the
stomach reacts reducing metabolite as vitamin C to
produce a high concentration of NO. Thus, allows
sterilization of swallowed food and to maintain a
gastric mucosal flow into blood [
20
].
NO is an obligate intermediate in the
denitrification pathway and it is converted to
nitrous oxide by the activity of NO reductase
(NRs). NRs are molybdoenzymes that reduce
nitrate 󰇛
󰇜 to nitrite 󰇛
󰇜 in both mammals
and plants.
In mammals, the salival microbes take part in
the generation of the 
 from 
, which
further produces NO in the presence of nitrite
reductases (NiRs) [
21
].
NO diffusion tubes could be used as a spray in
absence of consumers to fumigate food locals,
modifying air conditioning could add protecting
ventilation, airplane, etc.
Physiological NO production by adding to diet
of arginine, presently used as a dietary supplement
by bodybuilders because can potentiate the
physiological role of NO, dilating blood vessels,
improving circulatory systems and muscular

7
development, potentially can improve sports
performance and muscle recovery.
Arginine role in aging
At the end of the eukaryotic chromosome,
long repetitive DNA strands (telomeres) are
configured. Aging produces its shortening, which is
correlated with chronic pain and phobic anxiety.
Telomeres shortening in atherogenesis leads to
investigate telomerase, a RNA-directed DNA
polymerase, which extends the telomeres of
eukaryotic chromosomes.
Nitric oxide (NO) is a reactive free radical that
regulates transcription of genes involved in
development, metabolism and differentiation. Is has
been shown that NO activates telomerase and may
have in endothelial cells a delay of senescence [
22
]
[
23
].
Endothelial cells (ECs) undergo a limited
number of cell divisions, stop dividing, and reach a
replicative senescence by acting as a molecular
clock. By the reactivation of telomerase, a cellular
reverse transcriptase could prevent telomere
shortening [
24
].
The endothelial isoform of the nitric oxide
synthase (eNOS) [
25
] effect on downstream
signaling of the catalytic subunit of human
telomerase reverse transcriptase (hTERT, for
understanding the pathogenesis and searching for
therapeutic approaches) and ERs, counteract the
process of endothelial cell aging [
26
] [
27
].
The telomeric repeat-binding factor 2 (TRF2)
is a protein that is present at telomeres but its
function, throughout the cell cycle, has been studied
for possible regulatory effect by arginine
methylation.
It is suggested that a restriction of senescence
progress could be approach, by incubation
procedures for Hb, to be used as a carrier of NO.
Consequently, adapts the NO saturation of Hb for
its in situ release to endothelial cells. Thus, allows
the gas exchanges, required for vasodilation of
blood vessels, in cardiovascular physiology. Exercise
improves endothelial function with produce NO,
which keeps blood vessels healthy.
Nascent Mg2+ compete by attracting water from
the shells of Na+/K+ allow sizing translocation
at the ions gates that support the membrane
potential
The erythrocyte as a carrier of the kosmotropic
 could function signaling for the capture of
water from the hydration shells of  and ,
fitting both into their gates, allowing across the
membrane the sieve effects, which confers specific
pattern of an action potential, contained in neuronal
junction’s vesicles to activate the NA activated-
adenylate cyclase (AC) located in the locus-
coeruleus.
This sieve effect potentiates the /-
translocation operating the membrane potential.
Mg2+ activates the / ATPase pump opening
the gates for  in and  out.
In response to a nervous impulse, their hydric
and dipolar states can change by dynamics of the H-
bonds could manifest discrete states of molecular
vibration, at . The brain maintains a steady
state in which small changes that last between 200
and 2000 ns do not alter the frequency. Quantum
mechanics describes them as wave, phonon. This
could be cycled as a vectorial function of hydric-
ionic translocation, participating into the active site
for enzyme state turnover. The energetic
contribution of the H-bond breakdown its value is
about: -5kcal/mol utilized to configure a
conformational change by mutual exclusion.
 [
28
] released activates the glutamate
neurotransmission [
29
]. Serotonin (5-
hydroxytryptamine, 5-HT) produced in Raphe
nuclei located in the brainstem, could induced 
increase and reduced the cAMP increase [
30
],
indicating cross-talk between the 5-HT-sensitive
 and cAMP pathways. Ionic equilibrium
controlling  effects for a simultaneous dead-
end by CaATP [
31
] [
32
] inhibition of adenylate
cyclase (AC) and mutual exclusion activation of the
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptor, first glutamate receptor ion
channel domain.
Turnover, with release of  from the
enzyme as a nascent ion  acquires a stronger
intrinsic charge.
The molecular kinetics synchronization that
prevents microscopic reversibility, because could

8
not be conceptually assimilated to the principle of
microscopic reversibility requiring a single door,
which could allow transit in both senses.
Mutual exclusion between hydrophilic and
hydrophobic domains allows vectorial kinetics,
which bypasses microscopic reversibility, due to the
enzymes turnover has only one sense the
hydrophilic changing conformation to the
hydrophobic one.
Figure 3: The mutual exclusion between oxyHb vs deoxyHb
allows Hb to be a carrier of O2 plus the hydration
shell of nascent Mg2+ released to activate the tissues demands for electrogenic action potential. The nascent Mg2+ tends to subtract
water from the hydration spheres of other ions, to complete their own. The incomplete octahedral geometry of the second hydric layers of
kosmotropic: (12H2O).[(6H2O).Mg2+] allows subtracting H2O from the hexagonal geometry in the first hydric layer of
[(6H2O).Na+] to configure an [(3H2O).Na+] a smaller size, which allows access to the its outside channel to transverse into
membrane inside to subtract H2O from the inside [(6H2O).K+], allowing its translocation to the outside. Thus, activating the Mg2+
required Na+/K+-ATPase.
Change conformation turnover of protein is
supported by the activation energy of broken H-
bonds, from polymeric water in cerebrospinal fluid
(CSF), conversion into waste water. Astrocytes [
33
]
could maintain the H-bond wasted state of water in
a liquid phase until their release as vapor to the
outside of the system, which is equivalent to
entropy dissipation.
Brain metabolism releases CO2 and H-bonds
breakdown thermogenesis are carried by air
and CSF respectively to dissipate entropy and
maximize the enthalpy potential through an
open system function
The myelin is a lipoprotein material that
constitutes complexes of phospholipid bilayers. It is
found in the nervous system of all vertebrates,
forming a thick layer around the axons of neurons
that allows the transmission of nerve impulses
between different parts of the body thanks to its
insulating power.
The glycation process requires the N-Acetyl-
D-glucosamine (2-Acetamido-2-deoxy-D-glucose,
D-GlcNAc) [
34
].
The process consists of adding a single N-
acetylglucosamine sugar to the serine or threonine
of a protein. This is a mean of either activation of
enzymes and transcription factors or deactivation by
a removal process.
In many animals, the olfactory bulb [
35
]
integrates motor function, which allowed their
offspring to reach self-care, in a short time.
After normal myelination in the utero,
myelination of the neonatal brain is far from
complete. In the column of Burdach, the first
myelination is seen as early as the 4 months of
gestation, but increases rapidly during 24th week.

9
Humans are born with an unmyelinated central
nervous system (CNS), which reach maturity in the
child 2 years old child.
In the human atrophy of the olfactory bulb
leads the loss of newborn baby brain motor
projections and under develop vision.
The lack of response of the sympathetic motor
system, to a signaling by the hypothalamospinal
tract, could not become consolidated until the
infant [
36
] learn to walk.
Myelin sheath wraps appears in the CNS in
spinal cord, brain and optic nerve. At the peripheral
nervous system (PNS), by the cytoplasm extension
of Schwann glial cells, wraps the oligodendrocyte
along neuronal axons.
The function of segmentation by Ranvier
nodes in between myelin sheets is to provide
localization of voltage gating Na+-channels, to allow
jumps of action potential. Thus, accelerates its
transmission along fine-tune circuits, differentiated
by the structural connectivity.
Myelin reduces the accumulation of charges or
capacitance of the axonal membrane at the Ranvier
nodes (1 micron unmyelinated section). In this the
action potential “jumps” following a nodes
sequence. At the axon terminal the action potential
releases the neurotransmitter at the synapses.
Insulating by myelin results in normal
operations of walking and the sensory system:
hearing, seeing and skin sensitivity.
Increasing myelination of the motor system
allows lifting the head, roll over, reach out and
crawl, and eventually walk and running. Learning
motor skills require practice, connecting the sensory
feedback by the spinal cord brain connection.
The myelin structural plasticity role in
cognition could restructure important brain
connections, by the myelination of axons.
Process improves by about 300% the velocity
of the action potential transmission. Also by myelin
isolation of an action potential pathway could
prevent the interference between neuronal circuits,
a noise equivalence, which facilitates learning and use
of interneuron signaling or language.
O-GlcNAcylation decline in the human brain
by aging is associated with cognitive decline. When
O-GlcNAcylation was increased in the
hippocampus of aged mice, spatial learning and
memory improved [
37
].
Synapsis plasticity
The learning mechanisms of Caenorhabditis
elegans (302 neurons) are simple. It detects and
memorizes an enormous diversity of stimuli: smells,
tastes, temperature, tactile sensations, and oxygen
concentration.
Its sensor cells connect with the interneurons
responsible for processing received information and
sending a response to the command neurons.
The neurons activated by a stimulus release
glutamate to the synapses, from a smaller number
of receptors, promoting the entry of calcium into
the neurons, which entails the fixation of memories.
But their structure is very similar to mammals, and
they function in learning, although they have
originated in remote periods of evolution.
Among the transcription factors, the cAMP
response element binding protein (CREB) stands
out. In humans, the CREB protein promotes the
formation of lasting memories, since it facilitates the
production of proteins that modify synapses [
38
].
Genetic vs environmental experiential learning
along the nurturing context of emotional
intelligence development
Genes account for between approximately
50% and 70% of the variation in cognition at the
population level.
A connectome is a comprehensive map of
neural connections in the brain, and may be thought
of as its “wiring diagram”. An organism's nervous
system is made up of neurons which communicate
through synapses. A connectome is constructed by
tracing the neuron in a nervous system and mapping
where neurons are connected through synapses.
During childhood, cognitive abilities
dramatically improve to make us who we are:
persons capable of multiple academic, social, and
professional activities [
39
].
Intelligence quotient (IQ) differences between
individuals have been shown to have a large
hereditary component. However, it does not mean
at groups-level exist evidence for a genetic
component between racial groups.
The results suggest a synchrony between
gender-related differences in the brain network and
behavior [
40
].

10
During nurturing conectomas for sex
differentiation had been characterized in men by
prefrontal to visual cortex and by transversal
connectivity in woman.
Stronger structural connectivity in motor,
sensory, and executive functions matched higher
spatial and motor skills in men. In the latter there is
an increase of neural connectivity within one
hemisphere of the brain. Thus, suggesting that
men's brains are structured to facilitate connectivity
and coordination between perception and action.
In women, there are stronger neural
connections between both cerebral hemispheres,
which would facilitate communication between the
analytical mind and intuition. In women, the
subnets associated with social cognition, attention
and memory showed greater connectivity, which
was consistent with higher cognitive-social and
memory skills in women than in men.
No differences have been found in the size of
the corpus callosum or in the white matter, which
allows the two sides of the brain to communicate
with each other.
Studies of human patterns resulting from
interaction of mother-infant separation, as related
with decreased glucocorticoid receptor gene
methylation of post-traumatic from early life stress.
In the newborn human, the residual structure
from evolutional deletion of the olfactory sense
allows a memory unable to coordinate muscles most
likely the sympathetic motor pathway has yet to be
integrated. This process requires a long period of
parental care, before reaching the brain structure of
neuronal circuits, capable to support muscular
interaction and development through a cognitive
visual-hearing language.
The locus coeruleus contains about   
noradrenaline-adenylate-cyclase (NA-AC) neurons
characterized by their very long axons reaching
almost every region. Thus, inputs from saliva at the
7TM receptors of AC, located at the rostral-oral-
cavity reach [
41
] the hypothalamic-pituitary-adrenal
(HTPA) axis controls on the psychosomatic
metabolic network. The increment of adrenaline
secretion [
42
] [
43
], but without entering the
cerebrospinal fluid (CSF) [
44
], shifts body
metabolism in the direction of depleting metabolic
reserves like fats and cortisol, releasing amino acids
from some brain proteins by gluconeogenesis
control. This mechanism is based in the absence of
negative feedback by adrenaline. The latter could
not cross the blood-brain barrier (BBB) and
therefore have only an incomplete control over the
inhibitory signaling, allowing to stop adrenal
secretion.
A metabolic perspective could explain the
function and structure thermodynamics advantage
of assigning to the brain, unchallenging nutritional
control of body metabolism for maximizing its own
development.
Thus, a brain pattern of emotional-hormonal
control, over metabolic supporting functions, may
participate on the psychosomatic bases of the
unconscious [
45
]. Thus, emotional rewards are
granted for human competitions adding a selective
control response to the primitive animal fight-or-
flight conditioning.
Hormonal glands secretion at the arterioles
irrigating the oral cavity could represent a near
autonomous hormonal signaling control of
behavior, through the emotional responses of the
oral-cavity-NA-AC-Hypothalamic (OC-NA-AC-
HT) axis.
Moreover, the sensorial 7TM hormonal
receptor structure of NA activated AC at the locus
coeruleus from distant regions, could integrate the
five senses (sound, smells, touch, visual and
gustatory regions) into simultaneous multiple
perception associated to emotional events.
The auditory cortex processes ear signals. The
neuronal network responses for attention, only
when the dorsolateral prefrontal cortex and a part
of the parietal cortex are simultaneously activated,
resulting in acoustic signals is more discernible
because of human ability to integrate the visual
perception of lips movement.

11
Figure 4: Emotional cognitive connection at the oral-cavity-hypothalamic-NA-AC-brain axis.
The
hypothalamus (bidirectional) receives projections from sympathetic motor system (carried by the hypothalamospinal tract and they
activate the sympathetic motor pathway), from the medial forebrain bundle carried by the mammillothalamic tract. Thus, notable
inputs are from the nucleus of the ventrolateral medulla and locus coeruleus.
The stimulation the frontal cortex
communication tie with the deep brain at the limbic
centers related to emotions, memory and learning of
the hyperactive depressed patients were calm down.
Thus, shows that reason and emotion are link by a
crossing turnover. The oral-cavity-hypothalamic-
brain axis appears to provide an alternative
therapeutic medication to the brain implantation of
electrodes. It is suggested a treatment localized at
vomeronasal organ (VNO) and/or the surrounding
palate areas with stimulatory procedures either:
electric discharge or pharmacological access to
hormones like oxytocin, dopamine, NA, etc.
Thalamus prevents sensorial signaling to reach
the cerebral cortex.
Synaptic strengthening is promoted by
oxytocin and dopamine for maternal cognitive
memory [
46
].
Oxytocin release into nucleus accumbens shell
is also activated by vaginocervical and lactation
stimulation.
The paraventricular hypothalamic area is the
source of oxytocin input into nucleus accumbens
shell, which is signal by dopamine for reward-
seeking behaviors.
Adrenaline, oxytocin and dopamine rewards
link the emotional responses, coupling with the
cognitive reasoning pathways originated at the
amygdala and the hippocampus.
Periodic breaks and breathing times at work do
the brain good. An important control center (the
prefrontal cortex) sends signals to deeper and older
brain regions: the hippocampus and the amygdala,
decreasing stress. This interaction favors the
transmission of social information, and the
development of selective recognition.
Function magnetic resonance image (fMRI)
studies, with participants, evaluated for the neuronal
activity of the hippocampus. The results showed an
inverse relation, differentiating between the task
measurements for predictability vs memory
functionality. Thus, indicating that both processes
compete for use of shared, limiting neurological

12
requirements. However, these could be not only
structural, but functional like metabolic ones,
thermogenic dissipation, etc. Hence, responding to
homeostatic controls.
The human brain could be characterized by
reflexive behavior of self-language interactions
rather than genetically triggered reflexes, which
appears to be hormonal configured, generating an
emotional intelligence.
Thus, lead to infer that opens a learning period
through emotional communication, which allows
humans to develop an emotional brain and
emotional intelligence. This event has evolved out
of genetic restriction, but responds to a pathway
introducing self-rewards feedbacks like
achievement. Thus, could emanate from
competition that human evolution consolidates
behavioral coupled to reasoning as an expectation
response for emotional reward.
Plasma-CSF
Figure 5: The choroid plexus epithelium (CPE)
generates cerebrospinal fluid (CSF) functions in
the mutual exclusive vectorial kinetic according
to a potential of hydrophilic-plasma to
hydrophobic-CSF flow.
 and 
 influx is
recycled across the membrane. At ventricular side, the
/-ATPase releases the . The -
cotransporter (KCC4) secretes  into the lumen containing
CSF. Luminal  is required for sustained CSF secretion.
Secretion by the AQP1, AE2 and NCBE at a
//
 ratio of 18:15:3 transports ions
taken up from the basolateral membrane.  into the
CSF enter via NKCC1 (--2 cotransporter) to
keep and mediate the bidirectional transport of ions gradients
of blood vs CSF and is regulated by SPAK (Ste20/SPS1-
related proline-alanine-rich protein kinase). Net ion
movement from the blood to the CSF creates a small
osmolarity between both compartments [
47
], retaining in
plasma polypeptides.
The brain of the newborn enjoys a hormonal
system development involving about 60% of total
calories ingested, which became stabilized at adult
age as 25% of total body energy.
Water is subsequently “dragged” via osmotic
forces across the epithelium and traverses the apical
membrane of the choroid plexus epithelial cell
through AQP1 (aquaporin) in both the luminal and
basolateral membranes.
At maturity the contributions of the H-bond energy,
by the enzyme hydration vs dehydration turnovers,
adds to a thermogenic flow of energy, which
requires that the brain develops an autonomous
cooling system. Thus, at the blood-brain (150ml
CSF) barrier are maintained permanently, and 0.3-
0.4 ml/min CSF are renovated constantly to
generate about 500ml/daily output. The equivalence
H-bond contribution is 󰇛󰇜 for each water
cluster configuration about
3.4x5kcal/mol=17kcal/mol.
The thermodynamics relationship between
structure and function requires an astrocytes
network [
48
] [
49
] for circulation after breakdown of
H-bonds.
Astrocytes are cells with actin filaments in the
cell’s skeleton, which impulses the CSF flux along
the glial network for pulsatile propulsion and the
support of the metabolic needs of the neurons. Also
its handedness transport entropy and potentiate
learning. Smaller entropy magnifies the enthalpy
potential.
The water clusters exhausted at the H-bond
transition of hydrated negative R groups in
polypeptide dynamics of folding in oxyHb are in
mutual exclusion with the dehydrated positive R
groups in deoxyHb. Accordingly, the circulation
sense, decreasing oxygenation, continuously

13
depletes H-bonds energy until reaching a choroid
plexus epithelium to generate CSF, but its
circulation requires a liquid state. Thus, allows a
non-polar kinetic strain between orbitals to
conform a resonance state at the water dimer
󰇛󰇜 integration.
The adenylate cyclase vectorial system
The RARE BiBi mechanism shows a second-
order dependence on substrate concentration:
 shows an obligatory step to bind first to
activate a site, allowing a binding site for MgATP.
Hence, the noradrenaline (NA) activated of the
hypothalamic tissue is controlled by obligatory ions
 exceeding the substrate concentration. The
cAMP and calmodulin release of Ca2+ determine
signaling of the amplitude, phase and period of
circadian rhythms [
50
].  and chelating
metabolites decreases CaATP, strongly activating
adenylate cyclase (AC) to increment the cAMP-
dependent activation of pathways for memory
affirmation.
The feedback inhibitory response to 
occurs after cAMP product has been synthetized in
condition needing to the expulsion of water from
the hydrophobic enclosure. The rupture of this
enclosure by the mass action of water cluster will
liberate cAMP. This leads to vectorial kinetic
because prevent the reentrance of cAMP into a
kinetic equilibrium, because the active site has
collapsed. Restructuration requires the hydrophilic
obligatory step. Thus, turnover requires various
folding steps, all irreversible by consuming H-
bonds. Each kinetic step configures the
reorganization of new folding structures because the
hydrophilic sequence is always exergonic and
involves the MgATP cleavage to generate
pyrophosphate and AMP- by about -8kcal/mol. The
AMP cycling to generate cAMP is endergonic by
about +10kcal/mol. The hydrophilic step evidently
could not contribute that enthalpy, but the folding
conformation of a hydrophobic cavity involves the
H-bond breakdown and expulsion of water.
Moreover, in order to release cAMP is needed the
mass action of water cluster. The polypeptide
changes in folding sum-up to several doors,
mutually exclusive, because the sense changes add
up as an opening step in the exergonic direction,
only after H-bond has been expended to
randomness, preventing a return.
NA (noradrenaline) release by the long axons
of the corpus coerellus into the synaptic junctions
also contributes to up-regulation of adenylate
cyclase (AC) by  and is turning off by .
As open system the accumulated mass action
of substrate over dissipative product allows to a
human brain to maximize neuronal transmission at
a much clear potential overcoming the kinetic
energy at a homeostatic temperature.
Adrenaline is coupled to the active site in
transfer to AC that is coupled to 7TM G protein
receptors [
51
] activated by a GTP cycle [
52
] [
53
]. NA
is released by the long axons of neurons [
54
] of the
locus-coeruleus into the synaptic junctions for
sensorial-integrated perception between many brain
areas. The activation of the /-ATPase pump
[
55
] release nascent , by decreasing 󰇟󰇠,
which has an inhibitory effect on AC.
Mg-cAMP turn-on/off of switch for CREB
function
Mg-cAMP binds to coordinate to both DNA
chains by coordination to the negatively oxygen of
phosphate groups, on both backbones, connecting
the repeated pattern of sugars and on that of cAMP.
The phosphoryl groups of the open DNA
structure are now facing with their charged oxygen
󰇛󰇜 to the inside to bind coordinately to 
[
56
].
The cAMP-Mg-DNA complex acts as a
physiological process. The insertion of 3’-
5’cyclicAMP of phosphoryl groups by coordination
of Mg2+ to the negative charged oxygen, to face the
hexahydrated Mg2+ and allowing the DNA chains to
rotate for the purine and pyrimidine groups to face
outwards.
The catabolite activator protein (CAP)
functions by binding in the presence of the
allosteric promoters and enhances the ability of
RNA polymerase holoenzyme (RNAP) to bind and
initiate transcription [
57
]. The cAMP induced Mg2+-
dependent open DNA configuration could
represent in working memory, the role of a short-
term memory intermediate stage.
In molecular biology, extracellular signal-
regulated kinases (ERKs) or classical MAP kinases
are widely expressed protein kinase intracellular

14
signaling molecules that are involved in functions
including the regulation of meiosis, mitosis, and
postmitotic functions in differentiated cells. Many
different stimuli, including growth factors,
cytokines, virus infection, ligands for heterotrimeric
G protein-coupled receptors, transforming agents,
and carcinogens, activate the ERK pathway. The
term, “extracellular signal-regulated kinases”, is
sometimes used as a synonym for mitogen-activated
protein kinase (MAPK), but has more recently been
adopted for a specific subset of the mammalian
MAPK family.
In the MAPK/ERK pathway, Ras activates c-
Raf, followed by mitogen-activated protein kinase
kinase (abbreviated as MKK, MEK, or MAP2K)
and then MAPK1/2.
Anti-inflammatory and analgesic effects of
Traditional Chinese Medicine Qianghuo Shengshi
decoction (QSD) may be achieved by regulating the
MAPKs protein and further regulating the
expression of the cAMP response element binding
protein (CREB) [
58
]. The level of intracellular cAMP
and the protein level of p-CREB, p-AKT, p-PDK1
and PKA protein were up-regulated after the
treatment of SNH compared with OGD/R
modeling [
59
].
Ras is typically activated by growth hormones
through receptor tyrosine kinases and GRB2/SOS,
but may also receive other signals. ERKs are known
to activate many transcription factors, such as
ELK1 and some downstream protein kinases.
The protein kinase Hippo signaling pathway
[
60
] that controls organ size in animals through the
regulation of cell proliferation and apoptosis.
The figure shows that Mg-cAMP inserted in
domain of DNA allows a switch-on by  and -
off by . A dynamic mechanism to activate gene
expression in CREB, by inducible gene response to
dopamine phosphorylation, via G protein coupled
receptor. Thus, acting to synthetize brain derived
growth factor, a regulator during neuronal
development and synaptic plasticity [
61
]. Thus,
producing neurotrophins and nerve growth factor,
related of inducible gene expression [
62
]. The D1-
like dopamine (DA) receptors act signaling
activatory stage to intracellular pathways. Activation
of MAP kinases in neuronal and endocrine cells is
critical for cell differentiation and function. This
action requires guanine nucleotide exchange factor
(GEF)-mediated activation of downstream a host of
Ras family small GTPases, which lead to Ras-Raf-
MEK-ERK (MAPK/ERK), is a chain of proteins
within cell [
63
] [
64
] that communicates a signal from a
receptor on the surface of the cell to the DNA in
the nucleus of the cell.
DHEA is an endogenous steroid hormone
precursor the human levels declines by aging. It is
one of the most abundant circulating steroids in
humans. DHEA is produced in the adrenal glands,
the gonads, and the brain [
65
]. It functions as a
metabolic intermediate in the biosynthesis of the
androgen and estrogen sex steroids both in the
gonads and has a variety of biological effects,
binding to nuclear and cell surface receptors acting
as a neurosteroid and modulator of neurotrophic
factor receptors. It is essential for the biosynthesis
of the glucocorticoids such as antiglucocorticoid
(cortisol) effects and for its actions on both
androgen and estrogen receptors, may function as a
therapeutic of high levels of inflammatory diseases,
or where adrenal production is altered, or addition
as a supplement in the diet for ancient peoples.
DHEA and/or DHEA-S may in fact be
phylogenetically ancient “ancestral” ligands of the
neurotrophin receptors from early on in the
evolution of the nervous system, and with multiple
aspects of immune function and supportive of
immunocompetence [
66
].
An emotional functioning brain develops
under nurturing by reward hormonal conditioning
by dopamine could be expected from the cAMP
release by AC hormonal stimulation. The cAMP
response element binding (CREB) protein became
phosphorylated via G protein coupled receptors
(GPCR) by dopamine signaling. The release of
stimulated a brain growth factor (BDNF) a
neurotrophin during neuron development became
involved in synaptic plasticity. Dysregulation of
GPCR signaling has been reported as involved in
early stress models, leading to aberrant emotionality.

15
Figure 6: Crystallographic data has been used to illustrate a structure of the CREB B-ZIP protein
domain, in which a hexahydrated Mg2+ ion binds with additional cAMP binding opens the double-
stranded DNA containing the consensus CRE sequence (5’-TGACGTCA-3’).
This ZIP domain could acquire
the double-stranded separation because the phosphoryl group of the nucleotide of the chain would rotate to face the hexahydrated
Mg2+. Each one of the purine groups would be facing outwards and allow the binding of the cAMP through its negative charged
oxygen in the cyclic configuration of its phosphoryl group.

16
Figure 7: Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid with immune and
metabolic regulatory properties, and its level markedly declines with increasing age in humans.
G
protein-coupled estrogen receptor (GPR30), protein kinase A (PKA), the LKB1-AMPK pathway: metabolism
and growth control in tumor suppression, 5' AMP-activated protein kinase or AMPK.
Figure 8: Producing neurotrophins and nerve growth factor, related of inducible gene expression. The
D1-like dopamine (DA) receptors act signaling activatory stage to intracellular pathways.
Activation of
MAP kinases in neuronal and endocrine cells is critical for cell differentiation and function. This action requires guanine nucleotide
exchange factor (GEF)-mediated activation of downstream a host of Ras family small GTPases, which lead to Ras-Raf-MEK-
ERK (MAPK/ERK), is a chain of proteins within cell that communicates a signal from a receptor on the surface of the cell to the
DNA in the nucleus of the cell.

17
CREB regulates transcription of genes: c-fos,
BDNF, tyrosine hydroxylase, numerous
neuropeptides (such as somatostatin, enkephalin,
VGF, corticotropin-releasing hormone), and genes
involved in the mammalian circadian clock (PER1,
PER2).
Mg-cAMP inserted in domain of DNA allows
a switch-on by  and –off by . A dynamic
mechanism to activate gene expression in CREB by
inducible gene response to dopamine
phosphorylation via G protein coupled receptor.
Thus, acting to synthetize brain derived growth
factor, a regulator during neuronal development and
synaptic plasticity.
Figure 9: Physiological mechanism for cAMP fitting into the double strands unzipping of nuclear DNA
or the transitory structure of cffDNA.
The non-physiological treatment technic of heating DNA at allows the
strands separation and transcription used experimentally. a) Base sequence of the two chains attracted to match in a double stranded
binary rotational symmetry of DNA. b) cAMP unzipping mechanism opens the double-stranded DNA structure positioning the
outside purines and pyrimidines bases to transcription mechanism leading to protein synthesis.

18
Physiological mechanism for cAMP fitting into
the double strands unzipping of nuclear DNA or
the transitory structure of cffDNA. The non-
physiological treatment technic of heating DNA at
 allows the strands separation and transcription
used experimentally. a) Base sequence of the two
chains attracted to match in a double stranded
binary rotational symmetry of DNA. b) cAMP
unzipping mechanism opens the double-stranded
DNA structure positioning the outside purines and
pyrimidines bases to transcription mechanism
leading to protein synthesis.
Figure 10: Cyclic GMP (cGMP) produced by
guanylyl cyclases the erythrocyte transport
cGMP
by its uptake from extracellular fluid,
without having in situ them enzyme.
Phosphodiesterases-5 (PDE5) breakdown cGMP in smooth
muscle cells, platelets, gastrointestinal epithelial cells, and
Purkinje cells. Also binds to cGMP to cGMP-dependent
protein kinase (PKG), cGMP-gated cation channels, and
allosteric sites on PDE5. Cyclic GMP binding to PKG
activates the phosphotransferase to phosphorylate cellular
proteins involved in  homeostasis, lowering and
desensitization the effects of . This effect causes
relaxation of smooth muscle, decreased platelet aggregation,
and altered transport of electrolytes and water in the
gastrointestinal tract. PDE5 is phosphorylated in intact cells
in response to stimuli that elevate cGMP, but does not
response to elevation of cAMP.
The water pair hydrophobic structure
The interaction of 2s and 2p orbitals allows a
tetrahedral of 104.5 angles from two H atoms of
positive charge, potential energy barrier to rotation
of one of the water molecules with respect to the
other.
A    results from the 1s orbit bond strain
with  to form a sp orbital. The H-bond of two
water molecules, the partially positive hydrogen
atom  attracts the partially 2  negative charge
of one  to the other. The result in a dipole-dipole
attraction mediated by the in between H-bonded
distance       󰇛󰇜 0.177nm the
polarity strength in water 104kcal/mol. The same H
covalently to oxygen atom distance of 0.1nm is
about 110kcal/mol. An    and      
 as between complementary pairs cytosine
attracted to guanine separated by 0.27 to 0.3nm
spontaneously attracted to form    or
   by the unshared N or O electrons pairs.
The water molecules detached from these
intramolecular bonds within a protein become H-
bonded between them, in bulk water. The dipolar
state can induce transitive dipoles in other close
molecules. Liquid state of water clusters show a
half-life  to  . The average number is
󰇛󰇜. From liquid state (0.54kcal/g) a large
number of H-bonds have to be broken to become
vapor.
However, heat homeostasis at cerebrospinal
fluid (CSF) hydrophobic medium at the pressure
present in astrocytes, is able to maintain the release
of single molecule of water by H-bonds breakdown
and the hydric affinity disappears and allow a little
polar state to manifest aggregated by non-polar
interactions of   , indicating energy
configuration: 󰇛󰇜, between both oxygen
atoms. Thus, circulates within the astrocytes
network in a metastable state of high oscillatory
tension between the oxygen orbitals, between
surrounding hydrogen atoms tending to maintain
covalent stability. Water dimer is the most widely
examined water cluster. The turnaround angle
differentiates six different isomers of water dimers.
Hereby, RP isomers are illustrated in figure, the
potential planar resonance states, orbital-5  
 and orbital-9   , with
oscillatory potential   .
Thus, determines several possible states of
coherence. Hence, kinetic energy accumulates by
resonance amplification. However, in the CSF the
absence of  and  allows coherence and their
presence in the air induce a randomness
decoherence, into the oral cavity, generates the
exhaled vapor to the outside, decreasing entropy of

19
the organism and allows brain to operate electrical
impulses by the enthalpy potential of dissipative
entropy, approaching the kinetic irreversibility of an
open-system.
Ion pairs can form in the hydrophobic
interiors of globular proteins. The free energy of
solvation of an ion is so large (about 60kcal/mol)
that an isolated charged residue is never found in
the hydrophobic interior of a globular protein.
Figure 11: Two oppositely charged ions,
however, can form an ion pair.
The free energy
change for transfer of two oppositely charged residues from
water to the monopolar interior of a protein is about -
1kcal/mol. When the ion pair forms, the water molecules in
the solvation sphere of each ion are released to the bulk. Each
ion therefore loses its free energy of solvation, driving their
force for ion-pair formation the increase in the entropy of
water clusters, during formation of the ion pair.
The microwave regions of the electromagnetic
spectrum are radio waves, based in hydrogen level
1s orbital that has in energy difference of
polarization change spin flip, dividing in two the
energy barriers or electron density on the orbital
motion. Pauli exclusion to energy density level
allows movement only between tunneling is
exchanges in the two pair of the H-bond donating
and accepting water monomers 󰇛󰇜.
A more rigorous statement is that, concerning
the exchange of two identical particles, the total
(many-particle) wave function is antisymmetric for
fermions, and symmetric for bosons.
This means that if the space and spin
coordinates of two identical particles are
interchanged, and then the total wave function
changes its sign for fermions.
In the dimers has been determined to begin to
flip of the acceptor monomer followed by 180o
rotation about oxygen-oxygen bond. The
interchange orbital exclusion could be assimilated to
the Pauli’s exclusion resulting between energy level
(barriers).
The vibrational position results from intrinsic
magnetic dipole movements as carried to the
hydrogen spin. These jump interactions increase in
energy parallel and decrease with anti-parallel (spin
flip). The frequency 󰇛󰇜 of the quantum relationship
   detectable by this transition   
.
A water dimer is capable to expand Doppler
shifts and became a much broader H spectrum
when cooling CSF.
In dimers when the position of the 4H became
parallel (relative positions for H-bonds with
differential frequency emission). The magnetic
movements are antiparallel (spin flip) create
harmonics in resonances kinetic energy trapped
within the dimer structure. In this which of the
wave function of electron and proton overlap
because de  encompasses partially the proton
location. The structure could expand the energy
contend by vibration absorbing kinetic energy,
trapping in resonance maintaining coherence under
limit of pressure (microtubules) and temperature.
The dimers exhibit three distinct low barriers
to kinetic pressures over orbital displacement. This
resistance results in vibrational states, stabilized by
resonance.
Analysis of H atomic closeness distance for
electron and proton leads to a Pauli’s resistance to
configure the same quantum state and explain a
vibrational state shared at H atoms, forced to
partially share microscopic space at differential time
to elude the exclusion. Since the magnetic dipoles
unstable state represents the possibility to emit tiny
current loops, structuring the high energy reached
by the dipoles, within water pairs.
Discussion
Prigogine modeled life as an open system
capable of decreasing entropy. However, his
cosmological model was not dissipative but based
on a tendency for mass action equilibrium between
enthalpy and entropy.
Common knowledge describes a
thermodynamics system as open to the sun and
integrated to life dependent of  [
67
]. The
confluence of requirements should be evident in
terms that the sun evaporates water clusters:
󰇛󰇜 by separating the molecules integrated in
the complex and day-cycle allows the cooling for

20
the vapor condensing as rain and return to the water
cluster state.
The state of coordinative linked H-bonds
became a reactant with negative and amphoteric His
R groups to coordinate Me2+, associated to a
domain configuring a hydrophilic state to a protein.
Mutual exclusion by H-bonds breakdown leads to a
reconfiguration. The presence of the proline in the
polypeptide chains allows folding and displacement
to create a competitive for amphoteric R groups
and complemented by positive R groups domain to
create attraction for negative molecules, like
 , , etc., which configures a
hydrophobic or less polar state. Turnover from
hydrophilic to hydrophobic state is a repetitive
circular sense.
Thus, increasing rotational and vibrational
kinetic activity, on the separated individual H2O
molecules, but maintaining a liquid coherence,
during circulation within astrocytes until the lower
pressure at the vomeronasal organ (VNO) [
68
]
allows phase conversion to vapor, equivalent to
entropy dissipation. The summation of the energy
generated by metabolites and H-bond consumption
allows the brain thermodynamics to support high
ratios between metabolite concentrations and the
electrogenic action potential in the dissipative states,
within an open system.
The dissipative thermogenic H-bonds
breakdown within water cluster configures a
randomness increment when coupled to the
proline-dependent folding of a polypeptide, but
under experimental conditions the potential of an
irreversible process would be undetectable because
the protein concentrations could be  whereas
the mass-action of environmental water cluster
would be several millions higher.
Conclusion
Maxwell predicted from a simplistic
thermodynamics response to the randomness of
heat distribution, the absence of vectorial kinetics.
However, a role of structure and function become
evident by the findings on the function of CF1-
ATPase-Synthase, when characterized by
resolution-reconstitution and its purification. Thus,
develops a prediction for the structural pathway for
thermogenic flow from water clusters into its
singular molecules, in the vapor state and its
entropy exit. Thus, the opening and closing of
doors is inalterable by a microscopic memory of the
primary amino acid sequence of a polypeptide, and
its differentiable domains in response to
electrostatic and hydrophobic attractions. However,
when the proline-dependent folding became
coupled to water clusters functioning by H-bonds
breakdown, mediates changes in the folding tertiary
structure to respond to the dynamics of segment
inter-sliding. These ones determine vectorial
kinetics by approaching or distancing functional
configurations, mediating the microscopic sequence
of events within an active site. Moreover, the H-
bonds twists reconfigurations, never reach energy
equilibrium, because is irreversible by a dissipative
exit from the system by a heat randomness of
vapor.
The Pauli principle exclusion does not allow
two fermions to occupy the same quantum state.
Thus, within an atom, the electrons first lodge into
an unoccupied lower orbital, then-on the empty
levels up to threshold denominated Fermi distance.
Under BCS (Bardeen-Cooper- Schrieffer) model, a
within superconductor the electrons could not be
treated as individually repulsive particles. Thus, each
pair of particles does not behave like fermions, but
as bosons, another relation between energy and
matter, in which pairs of electrons could
agglomerate as a Bose-Einstein condensate. The
BCS derivative theories assume that in the boson
state interactions could be related to the electron
spins. The electron is not limited to orbiting a
proton because it also turns around its axis.
Accordingly, the movement of atoms became
differentiable from classical physics description as
solid, liquid and gasses. Furthermore, rotational
movement could take only one sense and therefore
automatically allows bypassing the microscopic
reversibility principle by allowing vectorial
dissipative potentials rather than tendency to only
relate to mass-action equilibrium.
Moreover, the rotation sense only limits one
possible sense, but creates two complementary
states denominated up and down. The latter,
predicts water pairs by opposite alignment of spins,
which could integrate shared orbitals.
Bosons have yet to be accepted for the
emergence of entanglement. However, this matter
to energy relationship predicts coherence-
decoherence states over the whole cosmos. But, if

21
so, the matter could be related to every
characteristic of the cosmological level.
A cosmological dissipative system is far from
equilibrium associated with the dissipative Planck
bosons energy [
69
] based in quantum mechanics as
inwardly open thermodynamics. This model meets
the challenge implicated by primordial gravitational
waves, which has only one turn around sense or
vectorial dimensioning of a self-contained universe.
The flow of enthalpy into the system would be
well above the generated entropy, which will exit as
vapor or singular dissociated molecules. Therefore
for all purposes the sliding turnover of the tertiary
structure could maintain structure-functional
changes, without truly affecting total free energy
(). The conditions reflect the energy state of the
polypeptide to have the dynamic of an open
molecular thermodynamic state because it operates
by the enthalpy input of a flow of H-bond
breakdown, vectorial directed to the outside of the
system.
Also may describe microscopic levels of
entanglement linkage between quantic energy. This
one allows superposition and uncertainty under a
discontinuous spatial microscopic structure of
energy. This becomes permissible if delocalization
results from a shorter time-causality than the one
required for encompassing a time coincidence of
microscopic events.
A variable span of time parameter fluctuation,
which delocalizes or not, the relationship between
energy and space would lead to uncertainty.
Unstable coincidence within available energy
flowing into available space could develop from the
Pauli’s principle of classic physics if could be
integrated with a quantum mechanics treatment.
Let’s consider that this means that orbitals
trajectories intertwine by compression at
temperatures compatible with life. This condition
allows evaluation of the kinetic energy absorbed to
form dimers 󰇛󰇜 from H-bond depleted
ones and circulates in liquid state, before that
released as vapor.
Analysis of closeness H atomic distance for
electron and proton leads to a Pauli’s resistance to
configure the same quantum state and explain a
vibrational state shared at H atoms level, forced to
partially share space at differential time eluding the
exclusion. Since the magnetic dipoles overlap,
represents the possibility to emit tiny current loops,
structuring the high energy reached by the dipoles,
within water pairs.
The conclusion is that the resonance between
two isomers of the dimer orbitals keeps energy into
the opposition between compressions and
distensions by quantum mechanism, preserving
vectorial kinetics.
The results should be lacking H-bonds
dissipated from water clusters: 󰇛󰇜, gain in the
degree of randomness and the system as a whole
pulled by opening the organismal system thanks to
entropy release.
The kinetics energy solvation provides a
polarity scale for unidirectional unitary sense of the
circulatory flow for the thermogenic transitions for
dissipation into the exit of organismal entropy.
Thermodynamically the complete process is a
cyclic one. A turnover from solar thermogenesis,
generating vapor, the kinetic equivalent of entropy
󰇛󰇜, which is dissipated by cooling and generates
enthalpy 󰇛󰇜, an Gibbs free energy:    
. Hence,  would be potentiated by dissipative
entropy, which results in an open system out of the
equilibrium.
Structure and function thermodynamics show
that chemical transitions are coupled by mass-
action, leading to equilibrium in a closed system. A
symmetry breaking has to appear to prevent
coupling between two differential forms of energy.
Thus, chemical affinity could not couple with the
randomness of the dissipative vector potential of
heat. The heat expulsion-out of the system, or
entropy, prevents integrative events.
The dead-end kinetic inhibition of adenylate
cyclase activity [
70
] [
71
] [
72
], which involves H-bond
breakdown of intermediates, does not manifest a
singular characteristic of a direct irreversibility, but
rather the incompatibility of dead-end inhibition
with the obligatory step because the active site
could not respond to a bidirectional transit at the
same time.
The turn-on, or turn-off, involves the
continuous reconstruction of the active site itself, an
obligatory step, or specific path for turnover, in
addition to the reactions intermediates to form
cAMP. Turnover involves a  activatory site
before binding the substrate Mg-ATP. The
integration with the coupling of , generating
the dead-end inhibition could not occur
simultaneously. The integration does require a

22
microscopic time vector to operate under
differentiated microscopic spatial relationships and
requires additional inputs of enthalpy.
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