A Computational Study of a Prebiotic Synthesis of a Tripeptide:
Thyrotropic Releasing Hormone (TRH)
NIGEL AYLWARD
BMS Education Services Company,
Sea Meadow House,
Road Town, Tortola,
BRITISH VIRGIN ISLANDS
Abstract: - Ab initio calculations are used to calculate the viability of a prebiotic mechanism for the synthesis
of L-proteins considered as a one-dimensional cooperative system having interlocking terms involving two
neighbouring amino-acid residues yielding the inter-bond energy, optimum conformation, and charge
distribution leading to an estimate of the secondary structure. The prebiotic synthesis of poly amino acids is
illustrated with the synthesis of a tripeptide, thyrotropic releasing hormone. The magnesium ion
metalloporphyrin complex is shown to bind the prebiotic stereospecific ligand precursors of the amino acids
proline, histidine, and pyroglutamic on the metal or nitrogen pyrrole sites as a two-site catalyst in their
copolymerization to form Glu-His-Pro-NH2. The order of addition of the monomers is the reverse of
pyroglutamylhistidinylprolamide to form the tripeptide. which is separated from the catalyst by hydrogen ions.
The reactions are feasible from the overall enthalpy changes in the ZKE approximation at the HF and MP2 /6-
31G* level, and with acceptable activation energies.
Key-Words: - Prebiotic stereospecific poly amino acid synthesis, thyroid releasing hormone.
Received: June 14, 2022. Revised: April 23, 2023. Accepted: May 16, 2023. Published: July 5, 2023.
1 Introduction
Computational chemistry has been used to
determine an estimate of the secondary structure, [1]
and tertiary structures of proteins, [2], [3], [4], from
protein sequence, by comparative homology
analysis, [5], and by incorporating machine learning
into quantum mechanical calculations, [6]. The
energy of a protein may be considered to have
interlocking terms which depend on conformations
of at least two neighboring amino acid residues and
is a one-dimensional cooperative system, [7].
Abinitio calculations may be utilized to calculate the
bonding energy and estimate the lowest energy
conformation for each of the added amino acids, [8]
to generate the entire sequence where each pair of
interlocking amino acids has an optimum
conformation leading to a predicted secondary
structure. A prebiotic mechanism is invoked to show
how stereospecific L- reactants could react to form
an L-protein. The calculations are used to justify the
mechanism with regard to enthalpy changes and
activation energies. The protein chosen to test the
mechanism and viability of the methodology is a
small protein thyrotropin releasing hormone (TRH).
The tripeptide, thyrotrophin-releasing hormone,
(TRH), is one of the simplest peptides, Glu-His-Pro-
NH2, [9], [10]. It is responsible for stimulating the
release of thyrotrophin (thyroid-stimulating
hormone, TSH) from the anterior pituitary gland,
[11], [12]. The main function of TSH is to control
the release of the thyroid hormones, thyroxine (T4)
and tri-iodothyroxine (T3) from the thyroid gland. A
feedback control of TSH secretion, either directly or
by inhibiting TRH, is exerted by T3 and T4, [12],
[13].
From a prebiotic perspective, [14], it is desirable
if the reactant molecules, derivatives of aziridones
formed spontaneously from a supposed prebiotic
atmosphere often held to have been originally
mildly reducing, [11], [15], implying the presence of
concentrations of carbon monoxide, ammonia,
water, and hydrogen. It has also been demonstrated
that porphin present from the time of
photosynthesis, [16], may act as a catalyst for the
formation of D-sugars, L-amino acids, [17], and
terpenes, [18].
This paper proposes a model for the catalytic
photochemically activated copolymerization of
substituted aziridone precurors of the amino-acids,
prolamide, [19], histidine, [20], and pyroglutamic
acid, [21], where the order of addition is the reverse
of Glu-His-Pro-NH2. Initiation of the
polymerization occurs at C-terminal prolamide end
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of the tripeptide, propagates through the histidine
residue, and terminates at the N-terminal of the
pyroglumate amino acid with separation of the
metal porphin catalyst. Molecules that have strained
structures such as aziridine, azetidine,
iminoethylene derivatives, and aziridones are easily
polymerized, [22], [23].
The synthesis of this biochemical tripeptide
hormone is postulated to be an example of a general
mechanism for the stereospecific prebiotic synthesis
of any polypeptide, presumed to be of the order of
23100, from the prebiotic era from stereospecific
aziridone precursors formed over a considerable
period of time.
The reactions described have been deduced as
kinetically and thermodynamically viable, but
photochemical excitation is required.
2 Problem Formulation
This proposed computational study of a plausible
synthesis of the tripeptide thyroid releasing hormone
(TRH)l involves the calculation of the enthalpy
changes for reaction intermediates in the ZKE
approximation and the calculation of activation
energies at the HF level. These activation energies
may all be accessible as the catalyst may absorb
appreciable photochemical activation, (0.21 h). The
computations tabulated in this paper used the
GAUSSIAN09, [24].
The standard calculations at the HF and MP2
levels including zero-point energy corrections at
the Hartree Fock level, [25], together with
scaling, [26], using the same basis set, 6-31G*.
are as previously published, [14], and activation
energies calculated at the HF level without scaling
are less accurate. All amino acids, dipeptide, and
tripeptide are of the L-configuration, [27].
If the combined energy of the products is less than
the combined energy of the reactants it may show
that the reaction is also likely to be spontaneous at
higher temperatures. This paper uses the atomic
unit of energy, the hartree, [24].
1h = 627.5095 kcal.mol-1.1h = 4.3597482 x 10-18 J
Mulliken charges are in units of the electronic
charge.
3 Problem Solution
3.1 Total Energies (Hartrees)
The formation of initial reactants is predicated on
the stereospecific formation of the prebiotic
aziridone precursors of the amino acids proline,
[19], histidine, [20], and glutamic acid, [21].
However, some initial modification of these
aziridones is required for the synthesis of this
unique tripeptide.
For prolamide to be present, the corresponding
aziridone, [19], or proline may react with ammonia
according to the reaction,
C5H9NO2 + NH3 → H2O +
proline (1)
prolamide, (2) C5H10N2O
ΔH = 0.00496 h
The histidine aziridone is unaltered from its
prebiotic synthesis, [20].
2-(4-iminazoyl methanyl) aziridin-3-one (3)
The final amino acid is pyroglutamic acid which is a
rare amino acid. Glutamic acid and its amide reach
an equilibrium in water, [28], to produce
pyroglutamic acid, as shown,
C5H9NO4 → C5H7NO3 + H2O
glutamic acid pyroglutamic acid
It is suggested that this rare amino acid was
formed from a cyclic imidine in the prebiotic
synthesis of the L-glutamic acid precursor as shown,
This may have occurred on the catalyst,
Mg.porphin, for activation energy, as,
1,2-(2-cyanoethyl) aziridine-3-one-1-yl →
(4)
N
H
CO-NH2
H
N
HC
CH
CH2
N
NH
O
NCO
N
H
N
CO
N
CH
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Mg.1,1-azabicyclo [5:1:0] 2-imido-6-keto hexan-
N1-yl.porphin (5)
ΔH = 0.00722 h
Hydrolysis of the imidine in aqueous solution
yielding the pyroglutamyl reactant as
Mg.1,1-azabicyclo [5:1:0] 2-imido-6-keto hexan-
N1-yl.porphin + H2O → NH3 +
Mg.1,1-azabicyclo [5:1:0] 2,6-diketo hexan-N1-
yl.porphin (6)
ΔH = -0.04983 h
Each of these aziridones may form adducts with the
catalyst on the metal and N-pyrrole sites. The
enthalpy of formation of the van der Waals complex
is small but it appears stable.
Mg.porphin is a powerful catalyst able to form
charge transfer complexes with a number of
different kinds of molecules, [29], [30].
With prolamide the ligand is positively charged
(0.08) and the porphin has a negative charge, [19].
The Mg-N bond is formed as shown,
Mg.porphin + prolamide →
Mg.1,prolamid-N1-yl.porphin (7)
ΔH = -0.04567 h
The charge on the prolamide adduct is -0.145
The Mg.1,prolamid-1-yl.porphin may be
photochemically excited for the prolamide to
migrate to bond with a pyrrole unit as a higher
energy adduct, [19], as shown,
Mg.1,prolamid-1-yl.porphin → (7)
Mg.1, porphin.prolamid-N1-yl (8)
ΔH = 0.12154 h
The charge on the adduct is -0.132.
For the above complex, where the adduct is
C4H8CONH2, the charge on the adduct ring nitrogen
is -0.767, and that on the amide nitrogen is -0.926.
For the corresponding zwitterion form,
C4H7CONH3, the charge on the ring nitrogen is -
0.768, and the amide nitrogen is -0.897.
The ring nitrogen is a plausible nucleophile and a
high-energy molecule.
The 2-(4-iminazoyl methanyl) aziridin-3-one may
also form two adducts with the catalyst on the metal
and N-pyrrole sites, as follows:
The enthalpy of formation of the van der Waals
complex is small but it appears stable.
Mg.porphin + 2-(4-iminazoyl methanyl) aziridin-
3-one →
(1) (3)
-
N
N
N
Mg
N
NCO
O
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Mg.1,2-(4-iminazoyl methanyl) aziridin-3-
one.porphin) (9)
ΔH = -0.04555 h
The charge on the adduct is 0.048.
A high-energy adduct may also be formed by
photochemical excitation as,
Mg.1, 2-(4-iminazoyl methanyl) aziridin-3-one (9)
→
Mg.1,porphin.2-(4-iminazoyl methanyl) aziridin-3-
one.porphin (10)
ΔH = 0.04596 h
The charge on the histidine adduct was -0.010.
The pyroglutamyl aziridone may also form stable
adducts as,
Mg.porphin + 1-azabicyclo [5:1:0] 2-6-diketo
hexane →
(11)
Mg.1,1-azabicyclo [5:1:0] 2-6-diketo hexan-N1-
yl.porphin (6)
ΔH = -0.04549 h
The charge on the pyroglutamyl adduct is -0.013.
The adduct may be excited to a stable excited state.
Mg.1,1-azabicyclo [5:1:0] 2-6-diketo hexan-N1-
yl.porphin (6) →
Mg.1,porphin. 1-azabicyclo [5.1.0] 2,6-diketo
hexan-N1-yl (12)
ΔH = 0.04763
The charge on the N-adduct was 1.239.
The first of these complexes on the metal site is
lower in energy than the corresponding complex on
the N-pyrrole site.
These complexes are integral reactants in the
proposed synthesis. The energies of the stable
complexes are shown in Table 1.
Table 1. MP2 /6-31G* total energies and zero point
energies (hartrees) for the respective equilibrium
geometries
__________________________________________
Molecule MP2 ZPE (HF)
hartree hartree
__________________________________________
proline (1) -399.92639 0.15591
prolamide (2) -380.07894 0.16902
2-(4-iminazoyl methanyl) aziridin-3-one (3)
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-470.85137 0.14092
Mg.1,2-(2-cyanoethyl) aziridine-3-one-1-yl (4)
-1562.81913 0.40300
Mg.1,1-azabicyclo [5:1:0] 2-imido-6-keto hexan-
N1-yl.porphin (5) -1562.81340 0.40465
Mg.1,1-azabicyclo [5:1:0] 2,6-diketo hexan-N1-
yl.porphin (6) -1582.68164 0.39156
Mg.1,prolamid-N1-yl.porphin (7)
-1565.24321 0.45725
Mg.1, porphin.prolamid-N1-yl (8)
-1565.20125 0.45638
Mg.1,2-(4-iminazoyl methanyl) aziridin-3-one-N1-
yl.porphin (9) -1656.01574 0.42940
Mg.1,porphin.2-(4-iminazoyl methanyl-aziridin-3-
one-N1-yl.porphin (10)
-1655.96813 0.42754
1-azabicyclo [5.1.0] 2,6-diketo hexane (11)
-397.51741 0.10317
Mg.1,porphin. 1-azabicyclo [5.1.0] 2,6-diketo
hexan-N1-yl (12)
- 1582.63240 0.38975
pyroglutamylhistidinylprolamide (13)
-1248.66433 0.42603
Mg.1, 2-(4-iminazoyl methan-1-yl) aziridin-3-one-
N1-yl.porphin.prolamid-N1-yl (14)
-2035.73478 0.61020
Mg.1,histidin-N1-yl-prolamide.porphin (15)
-2035.95706 0.60949
Mg.1, porphin.histidinyl-N1-yl-prolamide (16)
-2035.81753 0.61210
histidinylprolamide (17)
-851.03735 0.31663
Mg.1, 1-azabicyclo [5.1.0] 2,6-diketo hexan-N1-yl
porphin.histidinyl-N1-yl-prolamide (18)
- 2433.21740 0.71639
Mg.1,pyroglutam-N1-yl.histidinylprolamide.
porphin (19) -2433.33380 0.72049
Mg.1,porphin.pyroglutam-N1-yl.histidinylprolamide
(20) -2433.38038 0.71741
Mg.porphin (1) -1185.12250 0.29262
OH. -75.52257 0.00911
OH- -75.51314 0.00885
H2O -76.19924 0.02148
NH3 -56.35738 0.03529
H2 -1.14414 0.01034
__________________________________________
3.2 The Overall Stoichiometry for the
Formation of the Tripeptide TRH
Although Mg.porphin is here taken as the catalyst
for the reaction, the overall stoichiometry to form
the TRH is comprised of the individual reactants to
form the three stereospecific primary reactant
amino-acids, as:
For the amino acid proline, [19], the prebiotic
synthesis has been given where the reactants listed
to make the non-zwitterionic acid may be formed
from simpler gaseous molecules as,
H-C ≡ C-C ≡ C-H + NH3 + CO + H2O + H2 →
C5H9NO2
ΔH = -0.17397 h
For the amino acid histidine, [20], a prebiotic
synthesis has been given where the reactants listed
to make the non-zwitterionic acid may be formed
from simpler gaseous molecules as,
NH2-CN + H-C≡C-C≡C-H + NH3 + CO + H2O →
C6 H9 N3 O2
ΔH = -0.16965 h
For the amino acid glutamic acid, [21], the prebiotic
synthesis has been given where the reactants listed
to make the non-zwitterionic acid may be formed
from simpler gaseous molecules as,
H-C≡ C-H + 2 HCN + H2 + CO + 3H2O →
C5H9NO4 + NH3
ΔH = -0.19326 h
The total stoichiometry for the formation of TRH
from its immediate precursors, prolamide, 2-(4-
iminazoyl methanyl) -aziridin-3-one and
pyroglutamyl aziridone, each formed from essential
prebiotic molecules, can then be written as,
prolamide + 2-(4-iminazoyl methanyl) aziridin-3-
one + 1-azabicyclo [5.1.0] 2,6-diketo hexane →
pyroglutamylhistidinylprolamide (Fig.1)
C5H10N2O + C6 H7N3O + C5H5NO2 →
C16 H22N6O4
Fig.1 pyroglutamylhistidinylprolamide (13)
ΔH = -0.20511 h
H
CO-NH2
N
NH
N
CH 2
CH
C
H
N
O
OC
NO
H
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The enthalpy change for the formation of each of
the aziridone precursors is negative and also the
formation of the final tripeptide is negative
indicating that this may be the energetically
favourable route to the initial formation of the
tripeptide.
The intermediates by which these stoichiometric
reactions may have occurred are as follows where
the first sequence involves the formation of the
histidinylprolamide.
ΔH = -0.10108 h
3.3 The formation of Mg.1, 2-(4-iminazoyl
methan-1-yl) aziridin-3-one.porphin.
prolamid-N1-yl
With a vacant magnesium coordination site 2-(4-
iminazoyl methan-1yl) -aziridin-3-one may form a
weak charge transfer complex with
Mg.porphin.prolamid-N1-yl as,
2-(4-iminazoyl methanyl) aziridin-3-one +
Mg.1,porphin.prolamid-N1-yl →
Mg.1, 2-(4-iminazoyl methan-1-yl) aziridin-3-one-
N1-yl..porphin.prolamid-N1-yl (14)
ΔH = 0.248966 h
The di-adduct is stable and the adduct charges are:
prolamide adduct 0.702, and the histidinyl adduct
0.022.
The charge of the prolamide ring nitrogen is -0.535,
and that of the amide nitrogen is -0.929.
For the histidinyl adduct the aziridone nitrogen has a
charge of -0.422, and the carbonyl carbon atom a
charge of 0.182. These charges are commensurate
with the formation of a peptide bond.
3.4 The formation of Mg.1,histidin-N1-yl.
prolamide.porphin.
The two adducts may coalesce as,
Mg.1, 2-(4-iminazoyl methan-1-yl) aziridin-3-one-
N1-yl..porphin.prolamid-N1-yl. →
Mg.1, histidin-N1-yl-prolamide. (15)
ΔH = -0.22291 h
The adduct carries a charge of 0.176.
The charge on the prolamide adduct ring nitrogen is
-0.771 and the amide nitrogen is -0.918. The
histidinyl nitrogen bound to the magnesium ion has
a charge of -0.440.
The activation energy to form the peptide bond was
calculated as, 0.015, whilst that for the reverse
reaction was 0.241.
3.5 The formation of Mg.1,porphin.
histidin-N1-yl.prolamide
The Mg.1,histidinyl-N1-yl.prolamidyl.porphin may
be excited by radiation to the higher N-adduct state
as,
Mg.1,histidin-N1-yl.prolamidyl.porphin →
Mg.1,porphin.histidin-N1-yl-prolamide (16)
ΔH = 0.14185 h
The adduct carries a charge of 0.914.
At this point in the synthesis the dipeptide,
histidinylprolamide could be released from the
catalyst according to the equation,
Mg.1,porphin.histidin-N1-yl-prolamide + H+ →
-
N
N
N
Mg
N
H
CO-NH2
N
H
NH
N
CH2
CH
C
HN
O
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Mg.porphin +
histidinylprolamide (17)
ΔH = -0.34486 h
The energy for the formation of the
histidinylprolamide dipeptide may then be
calculated as,
2-(4-iminazoyl methanyl) aziridin-3one +
prolamide → histidinylprolamide
ΔH = -0.10108 h
It is these inter amino acid bonding energies that
allow the energy of a protein to be calculated where
each bonding energy may be optimal from the free
rotation of the added amino acid as defined by the
rotation angles ψ and φ, [30]. As the adduct is
present as a high energy compound it may be able to
optimize the rotation angles allowing each
successive amino acid generated to attain an optimal
primary and secondary structure. The presence of
the catalyst does not greatly affect the rotations
where a slight preference for the L-amino acid
monomers to form a right-handed helix is expected,
[31]. For the corresponding
Mg.porphin,alanylalanine-1, the right-handed helix
(120,120) and the left-handed helix (240,240) are of
comparable energy (< 1kcal. Mol-1) The left and
right-handed generated helices are shown in Fig.2
for the Mg.porphin,alanylalanine-1 complexes.
Fig. 2: Left and right-handed generated complexes
of Mg.porphin,alanylalanine-1.
..
3.6 The formation of Mg.1,1-azabicyclo [5.1.0]
2,6-diketo hexan-N1-yl.porphin.histidin-N1-yl-
prolamide
A bicyclo[5.1.0] 2,6-diketo hexane (11) may form
an adduct with the vacant Mg.porphin binding site
as,
bicycle [5.1.0] 2,6-diketo hexane (11)
+ Mg.1,porphin.histidin-N1-yl.prolamide →
Mg.1, 1-azabicyclo [5.1.0] 2,6-diketo hexan-N1-yl
porphin.histidin-N1-yl.prolamide (18)
ΔH = 0.11855 h
The charge on the bicycle [5.1.0] 2,6-diketo hexane
adduct was 0.827, that on the histidin-N1-
yl.prolamide adduct 0.002.
3.7 The formation of Mg.1,pyroglutam-N1-
yl.histidinylprolamide.porphin
The Mg.1, 1-azabicyclo [5.1.0] 2,6-diketo hexan-
N1-yl.porphin.histidin-N1-yl-prolamide adducts
may coalesce as,
Mg.1, 1-azabicyclo [5.1.0] 2,6-diketo hexan-N1-yl
porphin.histidin-N1-yl-prolamide →
Mg.1,pyroglutam-N1-yl.histidinylprolamide.
porphin (19)
ΔH = -0.11275 h
The charge on the adduct was 0.601
H
CO-NH2
N
NH
N
CH 2
CH
C
HN
O
2
-
H
CO-NH2
NH
NH
N
CH2
CH
C
HN
O
OCO
N
N
Mg
N
NN
-
H
CO-NH2
NH
NH
N
CH2
CH
C
H
N
O
OC
N
N
Mg
N
NN
O
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3.8 The formation of Mg.1,porphin
pyroglutamylhistidinylprolamide.
The Mg.1,pyroglutam-N1-yl.histidinylprolamide.
porphin may be excited to a higher energy state as,
Mg.1,pyroglutam-N1-yl.histidinylprolamide.
porphin →
Mg.1,porphin.pyroglutam-N1-yl.histidinylprolamide
(20)
ΔH = -0.04933 h
The charge on the adduct was 0.0.942.
3.9 The formation of pyroglutamyl
histidinylprolamide.
The reaction of the Mg.1,porphin.pyroglutam-N1-
yl.histidinylprolamide with a hydrogen ion and
hydroxyl anion may free the tripeptide from the
catalyst as a neutral amide as,
Mg.1,porphin.pyroglutam-N1-yl.histidinylprolamide
→
pyroglutamylhistidinylprolamide (13)
ΔH = -0.40535 h
The potential energy diagram for this peptide
bonding is given in Fig.3. where the NH of
histidinylprolamide adduct acts as a nucleophilic
reagent to bond with the CO of the NH-bound
pyroglutamyl adduct.
Fig. 3: The nucleophilic histidinylprolamide is near
(2.4,1.6). The transition state with the electrophilic
pyroglutamyl adduct is near (1.6,1.3) and the
pyroglutamylhistidynylprolamide near (1.3, 2.1).
The formation of pyroglutamylhistidinyl prolamide
may then be given as,
1-azabicyclo [5.1.0] 2,6-diketo hexane + 2-(4-
iminazoyl methanyl) aziridin-3-one + 1-azabicyclo
[5:1:0] 2-6-diketo hexane →
pyroglutamylhistidinylprolamide
ΔH = -0.20511 h
The activation for peptide bond formation was
calculated as, 0.010 h, and for the reverse reaction
as, 0.236.
4 Conclusion
The surface catalyzed photochemically activated
copolymerization of the postulated prebiotic
aziridone derivatives for the amino acids proline,
histidine, and pyroglutamic acids provides a
plausible explanation for the formation of the
stereospecific tripeptide,
pyroglutamylhistidinylprolamide, according to the
laws of chemistry although the concentrations of
these molecules and the time for their prebiotic
synthesis is open to wide speculation, possibly
millions of years. However, the reaction of these
highly reactive molecules is assisted by the catalyst,
Mg.porphin, [17], available at the time of
photosynthesis, [16], providing a reduced entropy
change for reaction and a lowering of the activation
energy for each step in the sequence of reactions.
The mechanism used here of a co-polymerization of
prebiotic aziridones would enable the formation of
the possible 23100 different proteins for a typical
poly amino acid where the enthalpy change is
-
H
CO-NH2
NH
NH
N
CH2
CH
C
H
N
O
OC
NO
N
Mg
N
NN
H
CO-NH2
N
NH
N
CH 2
CH
C
H
N
O
OC
NO
H
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favourable and the activation energy smaller than
for a gas phase reaction of the free aziridones.
The high reactivity of the aziridones leads to their
self initiation, propagation and termination to form
polyamino acids. Although this mechanism has
used the catalyst as a two-site catalyst, Mg.porphin,
is really a five site catalyst well able to synthesize
aziridone derivatives in situ and simultaneously
form multiple growing peptides in a higher energy
state on its surface, and thereafter enable the mutual
termination of peptides to produce cyclic peptides
such as gramicidin S, [32]. Enzymes containing the
catalyst such as cytochrome-c do suggest that this
mechanism occurred, [33].
The aziridones are possible precursors of the
tRNAs, [11], of present biochemistry as highly
reactant with the 3’ OH groups of RNAs.
The co-polymerization of aziridones is expected to
yield life changing industries in synthetic protein
and bio-degradable plastics.
Further work at a higher accuracy may alter the
values given here.
Acknowledgement:
Appreciation is expressed to Gaussian Inc..
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