The molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: Post Hartree-Fock study of the DNA rare base pairs
Gas-phase gradient optimization of the DNA rare base pairs containing lactam-lactim and amino-imino tautomers was carried oat using the Hartree-Fock (HF), Density Functional Theory (DFT) and the second-order Moller-Plesset perturbation (MP2) methods at the 6-31G(d, p) basis set. It is shown that ful...
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| Date: | 2005 |
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Інститут молекулярної біології і генетики НАН України
2005
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| Cite this: | The molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: Post Hartree-Fock study of the DNA rare base pairs / V.I. Danilov, D.M. Hovorun, N. Kurita // Біополімери і клітина. — 2005. — Т. 21, № 1. — С. 70-79. — Бібліогр.: 21 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1860090108847325184 |
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| author | Danilov, V.I. Hovorun, D.M. Kurita, N. |
| author_facet | Danilov, V.I. Hovorun, D.M. Kurita, N. |
| citation_txt | The molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: Post Hartree-Fock study of the DNA rare base pairs / V.I. Danilov, D.M. Hovorun, N. Kurita // Біополімери і клітина. — 2005. — Т. 21, № 1. — С. 70-79. — Бібліогр.: 21 назв. — англ. |
| collection | DSpace DC |
| container_title | Біополімери і клітина |
| description | Gas-phase gradient optimization of the DNA rare base pairs containing lactam-lactim and amino-imino tautomers was carried oat using the Hartree-Fock (HF), Density Functional Theory (DFT) and the second-order Moller-Plesset perturbation (MP2) methods at the 6-31G(d, p) basis set. It is shown that full geometry optimization at the MP2 level leads to an intrinsically nonplanar propeller-twisted and buckled geometry of G*-T and G-T* base pairs. The nonplanarity of the pairs is caused by pyramidalization of the amino nitrogen atoms, which is underestimated by the HF and DFT methods. This justifies the importance of geometry optimization at the MP2 level for obtaining reliable prediction of the charge distribution, molecular dipole moments and geometrical structure of the base pairs. The comparison of the formation energies for the rare base pairs shows the energetical preference of the G*-T and A-C* base pairs as compared with the G-T* and A*-C ones, respectively. It is detected that the stabilization energies of the G-T* and A*-C base pairs describing the interaction between monomers are essentially larger than those of the G*-T and A-C* base pairs, respectively. An analysis of the decomposition members for molecular HF interaction energies by Morokuma-Kitaura (MK) and the Reduced Variational Space (RVS) methods showed that the nature of a larger stability of the G-T* and A*-C base pairs as compared to the G*-T and A-C* ones is due to the electrostatic interactions by 60–65 % and the polarization and charge transfer interactions by 35–40 %.
Здійснено газофазну градієнтну оптимізацію рідкісних пар основ ДНК, які включають у себе лактам-лактимні і аміно-імінні таутомери, за допомогою методу Хартрі-Фока (ХФ), теорії функціонала густини (ТФГ) та другого порядку теорії збурень Моллера-Плессета (МП2) у базисі 6-31G(d, р). Показано, що повна оптимізація геометрії на рівні МП2 веде до внутрішньо неплоскої пропелер-обертальної і вигнутої геометрії пар основ G*-T і G-T*. Неплощинність пар обумовлена пірамідалізацією атомів азоту аміногрупи, яка недооцінюється методами ХФ і ТФГ. Це виправдовує важливість оптимізації геометрії на рівні МП2 для отримання помірко ваного передбачення розподілу зарядів, молекулярних дипольних моментів і геометричної структури пар основ. Порівняння енергій формування рідкісних пар основ демонструє енергетичну перевагу пар основ G*-T і А-С* стосовно пар G-T* і А*-С. Виявлено, що величини енергій стабілізації пар основ G-T* і А*-С, які описують взаємодію між мономерами, значно більші за аналогічні значення пар основ G*-T і А-С* відповідно. Використовуючи аналіз членів розкладання ХФ енергій молекулярної взаємодії методами Морокуми-Кітаури і зменшеного варіаційного простору, знайдено, що природа більшої стабільності пар основ G-T* і А*-С порівняно з парами G*-T і А-С* на 60–65 % обумовлена електростатичними взаємодіями і на 35–40 % — поляризаційними взаємодіями і взаємодіями з перенесенням заряду відповідно.
Gas-phase gradient optimization of the DNA rare base pairs containing lactam-lactim and amino-imino tautomers was carried oat using the Hartree-Fock (HF), Density Functional Theory (DFT) and the second-order Moller-Plesset perturbation (MP2) methods at the 6-31G(d, p) basis set. It is shown that full geometry optimization at the MP2 level leads to an intrinsically nonplanar propeller-twisted and buckled geometry of G*-T and G-T* base pairs. The nonplanarity of the pairs is caused by pyramidalization of the amino nitrogen atoms, which is underestimated by the HF and DFT methods. This justifies the importance of geometry optimization at the MP2 level for obtaining reliable prediction of the charge distribution, molecular dipole moments and geometrical structure of the base pairs. The comparison of the formation energies for the rare base pairs shows the energetical preference of the G*-T and A-C* base pairs as compared with the G-T* and A*-C ones, respectively. It is detected that the stabilization energies of the G-T* and A*-C base pairs describing the interaction between monomers are essentially larger than those of the G*-T and A-C* base pairs, respectively. An analysis of the decomposition members for molecular HF interaction energies by Morokuma-Kitaura (MK) and the Reduced Variational Space (RVS) methods showed that the nature of a larger stability of the G-T* and A*-C base pairs as compared to the G*-T and A-C* ones is due to the electrostatic interactions by 60–65 % and the polarization and charge transfer interactions by 35–40 %.
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I S S N 0233-7657 . Біополімери і клітина. 2005 . T . 2 1 . № І
М О Л Е К У Л Я Р Н А Б І О Ф І З И К А
The molecular mechanism of the spontaneous
substitution mutations caused by tautomerism
of bases: Post Hartree-Fock study of the DNA rare
base pairs
V. I. Danilov, D. M. Hovorun, Noriyuki Kurita1
Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine
150 Acad. Zabolotnoho St . , Kyiv, 03143, Ukraine
Toyohashi University of Technology, Department of Knowledge-Based Information Engineering
Tempaku-cho, Toyohashi, 441-8580, Japan
Gas-phase gradient optimization of the DNA rare base pairs containing lactam-lactim and amino-imino
tautomers was carried oat using the Hartree-Fock (HF), Density Functional Theory (DFT) and the
second-order Moller-Plesset perturbation (MP2) methods at the 6-31G(d, p) basis set. It is shown that
full geometry optimization at the MP2 level leads to an intrinsically nonplanar propeller-twisted and
buckled geometry of G*-T and G-T* base pairs. The nonplanarity of the pairs is caused by pyramidalization
of the amino nitrogen atoms, which is underestimated by the HF and DFT methods. This justifies the
importance of geometry optimization at the MP2 level for obtaining reliable prediction of the charge
distribution, molecular dipole moments and geometrical structure of the base pairs. The comparison of the
formation energies for the rare base pairs shows the energetical preference of the G*-T and A-C* base pairs
as compared with the G-T* and A*-C ones, respectively. It is detected that the stabilization energies of the
G-T* and A*-C base pairs describing the interaction between monomers are essentially larger than those
of the G*-T and A-C* base pairs, respectively. An analysis of the decomposition members for molecular
HF interaction energies by Morokuma-Kitaura (MK) and the Reduced Variational Space (RVS) methods
showed that the nature of a larger stability of the G-T* and A*-C base pairs as compared to the G*-T and
A-C* ones is due to the electrostatic interactions by 60—65 % and the polarization and charge transfer
interactions by 35—40 %.
Key words: spontaneous mutations, tautomerism, rare base pairs, Hartree-Fock, DFT, Moller-Plesset,
geometry optimization, nonplanarity of amino group, propeller-twisted and buckled geometry, Morokuma-
Kitaura analysis, interaction energy, stability energy.
Introduction. One of the possible molecular mecha
nisms for the formation of spontaneous mutations is
conditioned by the tautomerism of DNA bases [ 1 ].
The tautomerism of bases can play an important role
in the formation of the Watson-Crick-like mismatched
base pair. There are two ways for the formation of the
rare base pairs from the tautomeric forms of DNA
bases: on the template level (replication errors) and
on the substrate level (insertion errors). If the
© V. I. DANILOV. D. M. HOVORUN. NORIYUKI KURITA. 2005
template residue or the incoming substrate (nuc
leoside triphosphate) is in the wrong tautomeric form
when DNA undergoes semi-conservative replication,
then incorrect base may be inserted. In case of the
absence of correction for this error before the next
replication cycle, the two daughter duplexes will have
different base pairs at the position of the original
mispair.
When forming a DNA double helix, guanine (G)
forms a H-bonded pair with cytosine (C). On the
70
THE MOLECULAR MECHANISMS OF THE SPONTANEOUS MUTATIONS
other hand, the rare lactim form of guanine (G*)
forms a pair with thymine (T) instead of C. Similarly,
the rare imino form of cytosine (C*) pairs with
adenine (A) instead of G. After the strand separation,
the counterbases will form pairs with A and T instead
of G and C, respectively.
Thus, the scheme postulated in ref. [1 ], leads to
a spontaneous G-C -* A-T transition in subsequent
rounds of replication, unless it is detected by the
methyl-directed mismatch DNA repair system. In its
turn A forms a hydrogen-bonded pair with T. Rare
imino tautomer of adenine (A*) forms pair with C
instead of T. The rare lactim form of thymine (T*)
pairs with G instead of A. After the strand separation,
the counterbases pair with G and C instead of A and
T, respectively. As a result it leads to a spontaneous
A-T -» G-C transition. In these cases the frequency of
mutations is governed by the concentration of tem
plate bases on DNA or free substrate nucleoside
triphosphates in their minor tautomeric forms in
solution.
Therefore spontaneous point mutations can arise
from errors during semi-conservative replication.
This, however, is very rare due to the exonuclease
functions as a proofreading mechanism recognizing
mismatched base pairs and excising them, but they
can escape at some frequency.
The tautomeric mechanism that does not require
the presence of the free rare tautomers in solution
may also occur. In this case the rare tautomers are
formed in the template via the simultaneous transfer
of two protons in the H-bonds of the DNA base pairs.
Based upon the Watson-Crick model of DNA, Lowdin
[2] pointed out that there was a certain intrinsic
probability of proton movement in DNA. Namely the
protons in two H-bonds between paired bases change
their position in time from the most favourable
position to the next most favourable position. This
spontaneous shift of the positions, which is charac
teristic and inherent to a quantum mechanical par
ticle, transforms both bases to their tautomeric forms.
The tautomeric form can make a pair only with a base
different from the normal partner.
This would cause an error in the genetic in
formation, and the accumulated errors of this kind
could be responsible for mutation, aging and spon
taneous tumors.
It should be noted that this modified tautomeric
mechanism equally with usual tautomerism assumes
that these tautomers will remain stable during DNA
unwinding and strand separation, which are the
prerequisite steps for the synthesis of new DNA
strand by polymerase. However, there has never been
any convincing evidence demonstrating that rare tau
tomeric forms of the bases are responsible for the
spontaneous mutagenesis. Recently Goodman sug
gested [3] that perhaps the rare base pairs exist in
the polymerase active site and later shift to the
ionized, protonated and wooble base pair structures
observed by NMR and X-ray crystallography.
Therefore, the ability to identify the rare base
pairs is not only interesting in itself but also may
open the way to investigate their properties in relation
to ionized and wooble base pairs. Moreover, ir
respective of that the rare base pairs is direct or
indirect reason of spontaneous mutations.
Very little information on the quantum chemical
study of the rare base pairs containing lactam-lactim
and amino-imino tautomers has been obtained up to
now. Some geometrical and electronic properties as
well as interaction energies disregarding the basis set
superposition error (BSSE), obtained at the HF/STO-
3G and HF/4-31G levels, were presented in the work
[4]. During the geometry optimization of the base
pairs, only the distances between the bases and their
mutual orientations were optimized whereas the cop-
lanarity of base pairs was maintained and the base
geometries obtained by the HF/STO-3G method were
kept rigid.
The interaction energies of the bases in the G*-T
and A-C* base pairs calculated by B3LYP/6-
31++G(d, p) method were presented in other works
[4, 5 ] . At the same time for the other two rare base
pairs (G-T* and A*-C) such data in [5] are absent.
Besides, the authors of these works [4, 5] proposed
that the interaction energy of the bases in the base
pairs is the index of the energetic preference of their
formation.
As a result the geometrical structure of DNA rare
base pairs, energetic aspects of formation and phy
sical picture of their H-bonded pairing with the
standard basis set are not yet determined. Moreover,
the influence of electron correlation on different
properties of the rare base pairs remains obscure. In
particular, the detailed analysis of nucleic bases
interactions at the HF and post HF levels of the
theory is extremely important.
This work presents the results of HF, DFT and
MP2 ab initio studies at 6-31G(d, p) level of a
number of properties of the rare base pairs (dipole
71
D A N I L O V V. ! . , H O V O R U N D . I . , N O R I Y U K I KUR1TA
moments, optimal geometries and interaction ener
gies) that have not been previously studied at these
levels of the quantum-mechanical theory.
Methods. In order to elucidate the above-men
tioned questions, we carried out a study of the G*-T,
G-T*, A*-C and A-C* rare base pairs at the HF level,
DFT level with functionals B3LYP and B3PW91 and
MP2 ab initio level to find stationary points on the
potential energy surfaces. In addition, the single point
calculations have been performed for the studied
systems at the MP2/6-311++G(d, p)/ /MP2/6-31G(d,
p) level of the theory.
The correlated calculations are performed within
the frozen core approximation [6]. The standard
split-valence 6-31G basis sets augmented by a set of
Cartesian d-polarization functions placed on heavy
atoms and p-polarization functions assigned to hyd
rogen atoms [6 ] were used for geometry optimization
of the rare base pairs at the HF, DFT and MP2 levels
of the theory.
The MP2 geometry optimization was started from
the HF/6-31G(d, p) optimized geometry of rare base
pairs [7 ]. Geometry optimization has been continued
until the largest component of gradient is smaller than
0.00003 Hartree/Bohr and the root means square
gradient is less than 1/3 of the maximal gradient
component. Since the intermolecular interaction ener
gy calculated in a finite basis set is a subject to a
BSSE, the calculated energy term should be appro
priately corrected. The counterpoise corrected MP2
formation energy for the H-bonded AB complex, E?,
from the usual form of the free base and the rare
tautomeric form of the free base is given by [7, 8 ]
Ef = ETAV + EDBf + E1NT, (1)
where
E™ = E (rare tautomer) - E (usual tautomer) (la)
is tautomerization energy;
E°Ef « ^ № 1
K a (AB_MP2) - E*F\ A(A_MP2) +
+ E*r\ B (AB_MP2) - £ * % B(B_MP2) (lb)
is the deformation energy describing the effects of the
geometry relaxation of subsystems A and B in the
dimer;
£*N T (AB_MP2) = E*r2M A B(AB_MP2) -
" E M P 2
A A B(AB_MP2) - £ M P 2 „ A B(AB_MP2) (lc)
is the MP2 stabilization energy of the base pair
describing the interaction between monomers.
According to the Moller-Plesset perturbation the
ory [9]
£ I N T = £ H F + £ . : O R ) ( 2 )
where
£H F(AB_MP2) = E"*^ A B(AB_MP2) -
~ £ " F A . A B ( A B _ M P 2 ) - E"\_ab(AB_MP2) (2a)
is the HF interaction energy between bases;
^ C O R = ^ N T { A B _ M P 2 ) _ £ « F (AB_MP2) (2b)
is the correlation interaction energy within the fra
mework of the second-order Moller-Plesset pertur
bation theory.
In the above-mentioned expressions the following
designations are used: £ ' Y z is energy of a system X
computed by the Y method with basis set Z. The
(AB_MP2) symbols indicate the geometry of complex
AB optimized by the MP2 method.
The £f term was corrected by the conventional
counterpoise correction method, which eliminates the
BSSE. The counterpoise corrected DFT formation
energy for the H-bonded AB complex is determined
by analogy with the MP2 formation energy. The E?
term in our analysis includes deformation energy £ J , E F
because monomers change their geometry upon for
mation of the complex. The £ D E F was calculated as the
difference between the energies of the bases in the
optimized dimer geometry and the optimized isolated
bases.
It should be noted that in the expressions (1),
(2) and (2a) the energy terms of the Hartree-Fock
interaction energy for the base pairs were calculated
on the MP2-optimized geometry since the Hartree-
Fock solution appears as the zero-order approxi
mation in the MP2 method (see [9]).
For the elucidation of the nature of the hydrogen
bonding and stability of the rare base pairs the
Morokuma-Kitaura (MK) [10] and the Reduced Va
riational Space (RVS) [11] methods of the decom
position for the molecular HF interaction energies
(£" F) were used. Different energy contributions de
termining hydrogen bonding in the rare base pairs,
namely the electrostatic energy, E™, exchange repul
sion energy, polarization energy, EFL, charge
transfer energy, E171, and the higher order coupling
term, were evaluated by these methods.
Since the intermolecular interaction energy cal
culated in a finite basis set is a subject to a basis set
BSSE, the calculated energy terms should be appro-
72
THE MOLECULAR MECHANISMS OF THE SPONTANEOUS MUTATIONS
•The HF values are given in parentheses.
priately corrected. The £" F , £ X R , £* : T, £ M I X energies,
the correlation interaction energy, £ C 0 R and total
complex formation energy, ET were corrected by the
conventional counterpoise correction method, which
eliminates the BSSE. It should be noted that the
BSSE correction is partially generated by the RVS
energy decomposition scheme for the £ X R , £fT and
£ ^ , x terms (see [12]).
All ab initio calculations were performed by the
GAMESS US set of programs ([13], Granovsky Alex
A. www http://classic.chem.msu.su/gran/gamess/in-
dex.html).
Results and Discussions. Table 1 summarizes
bond lengths and bond angles involved in hydrogen
bonds between the bases of the G*-T, G-T*, A*-C
and A-C* rare base pairs as well as dipole moments
based on the HF/6-31G(d, p) and MP2/6-31G(d, p)
geometry optimization calculations.
As seen from Table 1 the dipole moments pre
dicted by the MP2 methods are noticeably different
from those predicted at the HF level. It agrees with
the known fact that the HF approximation overes
timates dipole moments. According to the MP2/6-
31G(d, p) results, the inclusion of electron correlation
during the geometry optimization reduces the dipole
moment of the G*-T and G-T* base pairs by 10 %
and 11 %, respectively, in comparison with the dipole
moment values calculated by the HF method. A larger
reduction of the dipole moment is predicted by the
MP2 method for the A*-C and A-C* base pairs. This
reduction constitutes 27 % and 21 %, respectively.
The data obtained show that the neglect of
electron correlation certainly distorts the molecular
structures of the rare base pairs. Electron correlation
brings both subsystems closer to each other. This can
be seen from the decrease in the distances between
the atoms H and Y in X-H...Y intermolecular H-
bonds of the base pairs. At the same time according
to the MP2/6-31G(d, p) calculations the distance
between the atoms X and Y in the intermolecular
H-bond of the G*-T and G-T* rare base pairs for the
studied basis set reduces by 0.10—0.14 A and 0.10—
73
http://classic.chem.msu.su/gran/gamess/in-
DANILOV V. I.. HOVORUN D. I.. NORiYUKI KURITA
*A value equal to 360° corresponds to a planar amino group. Decline from the planar state serves as a piramidalizaton level.
0.11 A, respectively, in comparison with the HF
optimized geometry. Analogous decreases in the A*-C
and A-C* base pairs constitute 0.02—0.05 A and
0.14—0.15 A. This is rather a significant shortening
caused by the dispersion attraction, which is taken
into account by the MP2 method.
It is interesting to note that the bond lengths of
the same H-bonds of the stereoisomer mispairs con
taining rare tautomers of bases are noticeably dif
ferent. Especially it concerns 0-H. . .0 hydrogen bond
of the G-T* base pair and N-H...N hydrogen bond of
the A*-C base pair that are shorter by 0.2 A and
0.1 A, respectively.
The geometric data characterizing the amino
groups of bases for the rare base pairs optimized by
the post HF methods are given in Table 2 (the
numbering system corresponds to the IUPAC recom
mendations on Nomenclature of Organic Chemistry).
It can be seen that according to the MP2
calculations the amino group of guanine in the G*-T
and G-T* base pairs is essentially nonptanar. At the
same time the amino group of cytosine in the A*-C
and adenine in the A-C* base pairs is planar.
The analysis of the optimized molecular structure
for the G*-T and G-T* base pairs shows that the
amino group hydrogens of guanine deviate from the
base plane in the direction, opposite to the shift of the
amino group nitrogen atom (the sp 3-hybridized struc-
74
THE MOLECULAR MECHANISMS OF THE SPONTANEOUS MUTATIONS
Table 3
The geometrical and energetical (kcallmol) characteristics of hydrogen-bonded rare base pairs, obtained at the DFT(B3LYP/6-3JG(d,
p)), DFT(BPW91l6-31G(d, p)), MP2Il6-31G(d, p) and MP2/6-311++G(d, p)//MP2/6-3JG(d, p)-optimized geometries
ture of the nitrogen atom valence shell of an NH2-
group or the partial pyramidalization of the amino
group of the DNA base). Examination of the base
pairs structure suggests that the source of the nonpla-
narity is a geometrical peculiarity of the NH2 group
of guanine.
At the same time it should be noted that the DFT
approach suggests a very weak nonplanarity of the
amino groups of bases (see Table 2). As a result of
underestimation of the pyramidalization effect, the
DFT method leads to almost planar or perfect planar
structure for the rare (see Table 2) and canonical
base pairs (see, for example, [7]). It should be noted
that our results on the geometry optimization of the
rare base pairs by the HF/4-31G method without any
geometrical constraint (compare to ref. [4 ]) as well as
HF/6-31G(d, p) led to the planar structures.
Meanwhile the question about the nonplanarity of
the nucleic acid bases and base pairs may have
important consequences for the realization of the
particular structures of these compounds in various
molecular complexes. The potential biological im
portance of interactions involving nonplanar amino
groups of, bases was repeatedly stressed by Sponer et
al. in the corresponding reviews [14, 15]. The data
characterizing the molecular structure of the rare base
pairs that have been obtained in our calculations is of
interest. The geometry optimization conducted at the
DFT and MP2 levels leads to an intrinsically non-
planar canonical G*-T and G-T* base pairs (see
Table 3). In other words, the bases in a base pair are
not coplanar, instead they are twisted about the
hydrogen bonds that connect them.
As it is well known the orientation of individual
bases within each base pair can be described in terms
of propeller twist (PT) and buckle parameters [16]
which characterize the rotation of bases around the
long axis of a base pair and the inclination of mean
planes of bases with respect to each other. In fact, the
PT angle is the dihedral angle that defines the
noncoplanarity, and buckle angle is the dihedral angle
between bases along their short axis. PT and buckle
angles are secondary parameters, which simply des
cribe the imperfections, i. e. nonplanarity, of a given
base pair.
Especially noticeable are the angular charac
teristics of two base pairs (magnitudes of propeller
and buckle angles) obtained by the MP2 method (see
Figure, a and b). So the propeller angles between the
base planes consist of 10° and 5° for the G*-T and
G-T* base pairs, respectively, whereas the buckle
angles are 7° and 2°. Supposedly, the main reason of
nonplanarity of the G*-T and G-T* base pairs is
pyramidalization of the amino group of guanine. The
75
Structures of the rare base pairs determined by MP2/6-31G(d, p)
method: a — G*-T; b — G-T*
conventional p lanar s t ructure of bases , as would be
expected, gives only the coplanar type of H-pair ing.
Among other possible distortion factors of nonpla-
nar i ty of the pairs a re a wide variety of secondary
long-range electrostatic interact ions, involving the
hydrogen atoms bonded to ring carbon atoms, and
steric reasons (see more information [14, 15]) . T h e
refore the nonplanar i ty of isolated DNA rare base
pairs as well as that of the isolated Watson-Crick ones
(see [7]) is their intrinsic property. T h e propeller
base twisting and buckling in isolated rare base pairs
has been obtained without any attraction of the
stacking perturbation hypothesis that was marked
earl ier [7, 17] .
According to the geometric selection mechanism
of bases as a principal de te rminant of DNA rep
lication fidelity [17—20] the geometrical and electro
static properties of the polymerase active site are
likely to have a profound influence on nucleotide-
insertion specificities. This influence would strongly
favor the insertion of bases having an optimal geo
metry , such that the C 1 ' ( N 9 ) - C 1 ' ( N 1 ) distances and
bond angles most closely approximate those of the
Watson-Crick base pairs.
T h e detailed s tudy of the obtained geometric
characteristics for the optimized ra re and Watson-
Crick base pairs showed the following. T h e distance
between the bonds joining the bases to the deo-
xyribose groups in the G*-T a n d G-T* rare base
pairs is close to the corresponding canonical distance
in the G-C base pair, while this dis tance in the A*-C
and A-C* base pairs is close to that in the A-T base
pair. Moreover, in each pair of stereoisomers the
C l ' - N 9 and C l ' - N l bonds make an angle with
C l ' ( 9 ) -Cr ( l ) line that is close to the corresponding
values in one of the Watson-Crick canonical base
pairs. T h e analogous conclusion made earlier Topal
and Fresco [21 ] who studied each of the above-
mentioned rare base pairs by the model building and
showed that these pairs were sterically compatible
with a Watson-Crick helix. Therefore the formation of
the DNA rare base pairs with such geometry is
compatible with the geometric constraints of the
s tandard double helical DNA. If these mispairs were
to be incorporated in a s t anda rd Watson-Crick double
helix, the helix would not likely be highly distorted
and its stability significantly did not reduce.
At the same time it should be noted that the
experimentally detected the G-T , G-A, and C-A
mispairs have markedly different C I ' ( 9 ) - C I ' ( 1 ) dis
tances and glycosyl bond angles than those of the
A-T and G-C pairs. T h e striking geometric identity
of the Watson-Crick A-T and G-C base pairs is not
matched by the A-C protonated wobble and G - T
wobble base mispairs or by the G(ant i ) -A(syn) base
mispair. Therefore the geometric constraints imposed
on the substra te and template bases at the polymerase
active site a re not the only ones for incorporation of
the non-Watson-Crick base pairs in DNA.
In the Table 3 the values of the tautomerization
energy £ : T A U (see ( l a ) ) , deformation energy £PET (see
( l b ) ) , stabilization energy £ J N T (see ( l c ) ) , formation
energy I? (see (1)) a re also given. T h e comparison of
the formation energies of the canonical [7] and rare
base pairs (see Table 3) shows that the formation of
the Watson-Crick G-C base pair is most preferable
among all s tudied base pairs. At the same time the
formation of the G*-T base pair is more preferable
than the A-T one. T h e A-C* and G-T* base pairs a re
only slightly energetically less preferable than the
A-T base pair. T h e direct comparison of the computed
energies for two pairs of stereoisomers also shows the
energetic preference of the G*-T and A-C* base pairs
towards the G-T* and A*-C ones , respectively. Our
results led to the interest ing fact that the stability of
the G-T* base pair is much larger than that of the
canonical Watson-Crick G-C base pair (see [7])
which is considered at present as the largest among
all studied base pairs .
It is also seen from Tab le 3 that the stabilization
energy of the G-T* base pair is essentially larger than
that of the G*-T, irrespective of computation me
thods. However, for the formation of the G-T* rare
base pair the usual form of T must be replaced by
rare tautomeric form of T* that requires the energy
76
THE MOLECULAR MECHANISMS OF THE SPONTANEOUS MUTATIONS
N o t e . ED — energy decomposition scheme; MK — Morokuma-Kitaura energy decomposition scheme; RVS — reduced variational space
energy decomposition scheme, complex formation energy disregarding tautomerization energy ET - ET - ETAV.
consumption equal to 11.92—13.35 kcal/mol. Further
more, the formation of such base pair is accompanied
by expense of 6.13—8.09 kcal/mol of the deformation
energy describing the effects of the geometry rela
xation of its G and T* bases. As a result, the
formation of the G-T* base pair becomes energetically
less preferable than that of the G*-T one. Table 3
also shows that the stabilization energy of the A*-C
base pair is essentially larger than that of the A-C*.
On the other hand, for the formation of the A*-C
base pair the usual form of A must be replaced by
rare tautomeric form of A* that requires the energy
consumption equal to 12.06—13.72 kcal/mol. More
over, for the geometry relaxation of A* and C bases
in this base pair the expenses of 2.68—3.62 kcal/mol
are required. So the formation of the A*-C base pair
is energetically less preferable than that the A-C*
one.
Therefore, the obtained data directly show that
the calculated interaction energies of bases in the rare
base pairs are insufficient in order to characterize the
relative ease or difficulty of incorporating base pairs
into a double helix. In particular, it was done in the
work [4, 5 ] . An appreciably larger stability of the
G-T* and A*-C base pairs is of particular interest in
view of large similarity of their molecular structure to
the corresponding stereoisomers. For understanding
this result, the MK and RVS analysis of molecular
interaction energy components for the DNA rare base
pairs was carried out. The calculated values of these
components are given in Table 4. The analysis of the
decompositions terms showed that the nature of a
larger stability of the G*-T and A*-C base pairs, as
compared to those of the G-T* and A-C* ones,
respectively, by 60—65 % is due to the electrostatic
interactions. At the same time polarization and charge
transfer interactions also make considerable con
tribution (by 35—40 %) to a larger stability of the
above-mentioned base pairs. It should be emphasized
that according to the Table 4 the correlation in
teraction makes a noticeably larger contribution to the
stability of the G*-T and A-C* base pairs than to that
of the G-T* and A*-C ones. Therefore, a larger
stability of the G-T* and A*-C base pairs is not
related to the correlation interaction.
As a result of our calculations, the following
conclusion can be done. According to the energetical
point of view, the formation of the G*-T and A-C*
base pairs must lead to the spontaneous mutations
more often in comparison with the G-T* and A*-C
ones, respectively. The analysis of possible transitions
during the replication and insertion errors and the
obtained formation energies of the base pairs show
that energetically the most probable transitions are
those for which tautomeric transformations occur in
the G. The transitions for which tautomeric trans
formations occur in the C and T are less probable. In
other words, in the case of lactam-lactim and amino-
imino tautomerism the replication errors mostly lead
to the transitions G-C -» A-T, whereas the insertion
errors mostly lead to the transitions A-T -* G-C. The
transitions for which tautomeric transformations occur
in the T are even less probable. The least probable
transitions are those conditioned by tautomeric trans
formations in the A.
The obtained data might testify in favour of the
77
DANILOV V. 1., HOVORUN D. 1., NORrYtlKJ KlIRITA
possibility of origin of the spontaneous mutations due
to the tautomerism of bases. Unfortunately, the origin
of the spontaneous mutations is conditioned not only
by energy factors, but also by other reasons. Among
them are such important factors as the entropy and
the possible geometric selection mechanism in the
exonuclease active site, enhancing the excision of
non-Watson-Crick base pairs. So, the discussed prob
lem is in need of the further investigation.
В. І. Данілов, Д M. Говорун, Норіюкі Куріта
Молекулярний механізм спонтанних мутацій заміщення,
обумовлених таутомерією основ: ПостХартрі-Фоківське
вивчення рідкісних пар основ ДНК
Резюме
Здійснено газофазну градієнтну оптимізацію рідкісних пар
основ ДНК, які включають у себе лактам-лактимні і аміно-
імінні таутомери, за допомогою методу Хартрі-Фока (ХФ),
теорії функціонала густини (ТФГ) та другого порядку теорії
збурень Моллера-Плессета (МП2) у базисі 6-31G(d, р). Пока
зано, що повна оптимізація геометрії на рівні МП2 веде до
внутрішньо неплоскої пропелер-обертальної і вигнутої гео
метрії пар основ G*-T і G-T*. Неплощинність пар обумовлена
пірамідалізацією атомів азоту аміногрупи, яка недооціню
ється методами ХФ і ТФГ. Це виправдовує важливість
оптимізації геометрії на рівні МП2 для отримання помірко
ваного передбачення розподілу зарядів, молекулярних диполь
них моментів і геометричної структури пар основ. Порів
няння енергій формування рідкісних пар основ демонструє
енергетичну перевагу пар основ G*-T і А-С* стосовно пар G-T*
і А*-С. Виявлено, що величини енергій стабілізації пар основ
G-T* і А*-С, які описують взаємодію між мономерами, значно
більші за аналогічні значення пар основ G*-T і А-С* відповідно.
Використовуючи аналіз членів розкладання ХФ енергій молеку
лярної взаємодії методами Морокуми-Кітаури і зменшеного
варіаційного простору, знайдено, що природа більшої стабіль
ності пар основ G-T* і А*-С порівняно з парами G*-T і А-С*
на 60—65 % обумовлена електростатичними взаємодіями і на
35—40 % — поляризаційними взаємодіями і взаємодіями з
перенесенням заряду відповідно.
Ключові слова- спонтанні мутації, таутомерія, рідкісні
пари основ, Хартрі-Фок, ТФГ, Моллер-Плессет, оптимізація
геометрії, неплоска аміногрупа, пропелер-обертальна і вигну
та геометрія, метод Мороку ми-Кітаури, енергія взаємодії,
енергія стабілізації.
В. И. Данилов, Д. Н. Говорун, Нориюки Курита
Молекулярный механизм спонтанных мутаций замещения,
обусловленных таутомерией оснований: ПостХартри-Фоковское
изучение редких пар оснований ДНК
Резюме
Осуществлена газофазная градиентная оптимизация редких
пар оснований ДНК, содержащих лактам-лактимные и амино-
иминные таутомеры, с помощью метода Хартри-Фока (ХФ),
теории функционала плотности (ТФП) и теории возмущений
Моллера-Плессета второго порядка (МП2) в базисе 6-3lG(d,
р). Показано, что полная оптимизация геометрии на уровне
МП2 приводит к внутренне неплоской пропеллер-вращатель
ной и согнутой геометрии пар оснований G*-T и G-T*. Непло
скостность пар обусловлена пирамидализацией атомов азота
аминогрупы, недооцениваемой методами ХФ и ТФП. Это
оправдывает важность оптимизации геометрии на уровне
МП2 для получения разумного предсказания распределения
зарядов, молекулярных дипольных моментов и геометриче
ской структуры пар оснований. Сравнение энергий образования
редких пар оснований демонстрирует энергетическую предпоч
тительность пар оснований G*-T и А-С* относительно пар
G-T* и А*-С. Обнаружено, что величины энергий стабилизации
пар оснований G-T* и А*-С, описывающие взаимодействие
между мономерами, существенно больше аналогичных значе
ний пар оснований G*-T и А*-С соответственно. Используя
анализ членов разложения для ХФ энергий молекулярного
взаимодействия методами Морокумы-Китауры и сокращенно
го вариационного пространства, найдено, что природа боль
шей стабильности пар оснований G-T* и А*-С по сравнению с
парами G*-T и А-С* на 60—65 % обусловлена электростати
ческим взаимодействиями и на 35—40 % — поляризационными
взаимодействиями и взаимодействиями с переносом заряда
соответственно-
Ключевые слова спонтанные мутации, таутомерия, редкие
пары оснований, Хартри-Фок, ТФП, Моллер-Плессет, опти
мизация геометрии, неплоская аминогруппа, пропеллер-враща
тельная и изогнутая геометрия, метод Морокумы-Китауры,
энергия взаимодействия, энергия стабилизации.
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УДК 577.112.7
Надійшла до редакції 03.08.03
79
|
| id | nasplib_isofts_kiev_ua-123456789-155116 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 0233-7657 |
| language | English |
| last_indexed | 2025-12-07T17:22:35Z |
| publishDate | 2005 |
| publisher | Інститут молекулярної біології і генетики НАН України |
| record_format | dspace |
| spelling | Danilov, V.I. Hovorun, D.M. Kurita, N. 2019-06-16T09:19:26Z 2019-06-16T09:19:26Z 2005 The molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: Post Hartree-Fock study of the DNA rare base pairs / V.I. Danilov, D.M. Hovorun, N. Kurita // Біополімери і клітина. — 2005. — Т. 21, № 1. — С. 70-79. — Бібліогр.: 21 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.0006DF https://nasplib.isofts.kiev.ua/handle/123456789/155116 577.112.7 Gas-phase gradient optimization of the DNA rare base pairs containing lactam-lactim and amino-imino tautomers was carried oat using the Hartree-Fock (HF), Density Functional Theory (DFT) and the second-order Moller-Plesset perturbation (MP2) methods at the 6-31G(d, p) basis set. It is shown that full geometry optimization at the MP2 level leads to an intrinsically nonplanar propeller-twisted and buckled geometry of G*-T and G-T* base pairs. The nonplanarity of the pairs is caused by pyramidalization of the amino nitrogen atoms, which is underestimated by the HF and DFT methods. This justifies the importance of geometry optimization at the MP2 level for obtaining reliable prediction of the charge distribution, molecular dipole moments and geometrical structure of the base pairs. The comparison of the formation energies for the rare base pairs shows the energetical preference of the G*-T and A-C* base pairs as compared with the G-T* and A*-C ones, respectively. It is detected that the stabilization energies of the G-T* and A*-C base pairs describing the interaction between monomers are essentially larger than those of the G*-T and A-C* base pairs, respectively. An analysis of the decomposition members for molecular HF interaction energies by Morokuma-Kitaura (MK) and the Reduced Variational Space (RVS) methods showed that the nature of a larger stability of the G-T* and A*-C base pairs as compared to the G*-T and A-C* ones is due to the electrostatic interactions by 60–65 % and the polarization and charge transfer interactions by 35–40 %. Здійснено газофазну градієнтну оптимізацію рідкісних пар основ ДНК, які включають у себе лактам-лактимні і аміно-імінні таутомери, за допомогою методу Хартрі-Фока (ХФ), теорії функціонала густини (ТФГ) та другого порядку теорії збурень Моллера-Плессета (МП2) у базисі 6-31G(d, р). Показано, що повна оптимізація геометрії на рівні МП2 веде до внутрішньо неплоскої пропелер-обертальної і вигнутої геометрії пар основ G*-T і G-T*. Неплощинність пар обумовлена пірамідалізацією атомів азоту аміногрупи, яка недооцінюється методами ХФ і ТФГ. Це виправдовує важливість оптимізації геометрії на рівні МП2 для отримання помірко ваного передбачення розподілу зарядів, молекулярних дипольних моментів і геометричної структури пар основ. Порівняння енергій формування рідкісних пар основ демонструє енергетичну перевагу пар основ G*-T і А-С* стосовно пар G-T* і А*-С. Виявлено, що величини енергій стабілізації пар основ G-T* і А*-С, які описують взаємодію між мономерами, значно більші за аналогічні значення пар основ G*-T і А-С* відповідно. Використовуючи аналіз членів розкладання ХФ енергій молекулярної взаємодії методами Морокуми-Кітаури і зменшеного варіаційного простору, знайдено, що природа більшої стабільності пар основ G-T* і А*-С порівняно з парами G*-T і А-С* на 60–65 % обумовлена електростатичними взаємодіями і на 35–40 % — поляризаційними взаємодіями і взаємодіями з перенесенням заряду відповідно. Gas-phase gradient optimization of the DNA rare base pairs containing lactam-lactim and amino-imino tautomers was carried oat using the Hartree-Fock (HF), Density Functional Theory (DFT) and the second-order Moller-Plesset perturbation (MP2) methods at the 6-31G(d, p) basis set. It is shown that full geometry optimization at the MP2 level leads to an intrinsically nonplanar propeller-twisted and buckled geometry of G*-T and G-T* base pairs. The nonplanarity of the pairs is caused by pyramidalization of the amino nitrogen atoms, which is underestimated by the HF and DFT methods. This justifies the importance of geometry optimization at the MP2 level for obtaining reliable prediction of the charge distribution, molecular dipole moments and geometrical structure of the base pairs. The comparison of the formation energies for the rare base pairs shows the energetical preference of the G*-T and A-C* base pairs as compared with the G-T* and A*-C ones, respectively. It is detected that the stabilization energies of the G-T* and A*-C base pairs describing the interaction between monomers are essentially larger than those of the G*-T and A-C* base pairs, respectively. An analysis of the decomposition members for molecular HF interaction energies by Morokuma-Kitaura (MK) and the Reduced Variational Space (RVS) methods showed that the nature of a larger stability of the G-T* and A*-C base pairs as compared to the G*-T and A-C* ones is due to the electrostatic interactions by 60–65 % and the polarization and charge transfer interactions by 35–40 %. en Інститут молекулярної біології і генетики НАН України Біополімери і клітина Молекулярна біофізика The molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: Post Hartree-Fock study of the DNA rare base pairs Молекулярний механізм спонтанних мутацій заміщення, обумовлених таутомерією основ: ПостХартрі-Фоківське вивчення рідкісних пар основ ДНК Молекулярный механизм спонтанных мутаций замещения, обусловленных таутомерией оснований: ПостХартри-Фоковское изучение редких пар оснований ДНК Article published earlier |
| spellingShingle | The molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: Post Hartree-Fock study of the DNA rare base pairs Danilov, V.I. Hovorun, D.M. Kurita, N. Молекулярна біофізика |
| title | The molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: Post Hartree-Fock study of the DNA rare base pairs |
| title_alt | Молекулярний механізм спонтанних мутацій заміщення, обумовлених таутомерією основ: ПостХартрі-Фоківське вивчення рідкісних пар основ ДНК Молекулярный механизм спонтанных мутаций замещения, обусловленных таутомерией оснований: ПостХартри-Фоковское изучение редких пар оснований ДНК |
| title_full | The molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: Post Hartree-Fock study of the DNA rare base pairs |
| title_fullStr | The molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: Post Hartree-Fock study of the DNA rare base pairs |
| title_full_unstemmed | The molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: Post Hartree-Fock study of the DNA rare base pairs |
| title_short | The molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: Post Hartree-Fock study of the DNA rare base pairs |
| title_sort | molecular mechanism of the spontaneous substitution mutations caused by tautomerism of bases: post hartree-fock study of the dna rare base pairs |
| topic | Молекулярна біофізика |
| topic_facet | Молекулярна біофізика |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/155116 |
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