Download Molecular electrostatic potentials and Mulliken charge populations of DNA mini-sequences ´ R. Santamaria

Chemical Physics 227 Ž1998. 317–329
Molecular electrostatic potentials and Mulliken charge
populations of DNA mini-sequences
R. Santamaria ) , G. Cocho, L. Corona, E. Gonzalez
´
Instituto de Fısica,
UNAM, Apdo. Post. 20-364, Mexico D.F. 01000, Mexico
´
Received 14 March 1997
Abstract
Molecular electrostatic potentials ŽMEPs. are used to investigate the biochemical reactivity of DNA nucleic acid bases
ŽNABs.. As a complementary scheme, a Mulliken population analysis is performed to determine internal charge distribution
changes when nucleic acids take part in pair complexes and DNA mini-sequences. From the fact that MEPs are capable
enough for predicting the formation of different hydrogen bonded pairs among NABs, it is inferred that for these compounds
the electrostatic force plays a dominant role. Particular attention is paid to Watson–Crick dimers as they exhibit different
preferred sites for an electrophilic attack to these of single nucleic acids. Finally, from the mini-sequences studied here, it is
concluded that recognition of DNA segments proceeds at relatively short distances as a result of a poor influence of NABs
on sugar and phosphate fragments. All quantum mechanical computations are performed within the density functional
formulation. q 1998 Elsevier Science B.V.
PACS: 87.15.Kg; 87.15.By; 31.15.Ew
Keywords: Molecular electrostatic potentials; Mulliken populations; Reactivity; Nucleic acids; Density functional theory
1. The molecular electrostatic potential
The determination of the deoxyribonucleic acid
ŽDNA. chemical active sites becomes of great interest for understanding a variety of specific reactions
between DNA and other molecular fragments. In
turn, knowledge of the shape and relative locations
of chemical active sites allows for DNA chemistry
modeling.
A large number of studies indicate that molecular
electrostatic potentials represent a suitable quantum
mechanical tool for elucidating reactive centers w1–3x.
)
Corresponding author. E-mail: [email protected]
The molecular electrostatic potential ŽMEP. is defined as w4x
V Ž r . s Ý Zar< R a y r < y Hd 3 r 1 r Ž r 1 . r< r 1 y r < ,
a
Ž 1.
where Za and R a denote the charge and position of
nucleus a , respectively. Eq. Ž1. renders the electrostatic interaction between the unperturbed charge
distribution of the molecule and a positive unit charge
located at point r. Shortcomings from the application
of the MEP to studying reactivity, at the early stage
of the recognition process, are preponderantly due to
the inability of a point charge to indicate orientation
0301-0104r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.
PII S 0 3 0 1 - 0 1 0 4 Ž 9 7 . 0 0 3 2 0 - 0
318
R. Santamaria et al.r Chemical Physics 227 (1998) 317–329
of an incoming partner molecule w5x, and to the
approximation resorted to for computing the electron
density r .
Because of the long-range nature of the forces
involved in Eq. Ž1., interaction at far distances between a partner molecule and DNA is mostly dominated by the electrostatic force. However, as the
separation between both fragments decreases other
well-known relaxation forces must be taken into
account, such as those coming from mutual polarization, exchange of electrons, charge transfer, dispersion, etc. w6,7x.
Encouraged by the simplicity and general good
performance of the electrostatic potential scheme,
and within the accuracy limits of Eq. Ž1., we use the
MEP approach as a tool to explore the reactive field
of B-DNA nucleotides in a single strand configuration.
It is important to note that expression Ž1. is not
the only identity that relates the potential V with the
electron density r . In fact, the Poisson expression:
= 2 V Ž r . s 4 pr Ž r .
Ž 2.
leads to an alternative way to compute V from r .
Nevertheless, in this work, electrostatic potential
computations are done according to Eq. Ž1..
As a matter of further insight of DNA reactivity,
we consider of interest to also carry out a Mulliken
population w8x analysis on nucleotide sequences. Although such analysis may be arguable, for instance
net atomic charges are incapable of reproducing the
exact dipole moment w9x, it is clear that Mulliken
populations yield one of the simplest pictures of
charge distribution. On the other hand, while Mulliken charges render net atomic populations in the
molecule, electrostatic potentials yield the electric
field out of the molecule produced by the internal
charge distribution. Therefore, Mulliken populations
appear as a complementary tool to the MEP approximation for studying reactivity, and correlation between results from both schemes is expected.
In order to apply a MEP and Mulliken population
analysis, the use of accurate geometries is required.
Thus, in Section 2, we briefly describe the way in
which we generate DNA nucleotide sequences and
the quantum mechanical method to compute the
electron density r . In Section 3, population charges
and MEPs of nucleic acid bases and their pair com-
plexes in the gas phase are estimated, with the aim of
elucidating charge distribution changes of these compounds when they are incorporated into the DNA
helix. At the second part of Section 3, we discuss the
same features for the case of single mini-strands of
B-DNA. Finally, Section 4 gives the main conclusions derived from a MEP and Mulliken population
analysis on the different DNA fragments, and the
corresponding expectations for the whole DNA system.
2. Geometries of the B-DNA nucleotide sequences
The large size of DNA prevents the application of
any accurate quantum mechanical method to determine its structure and electronic properties. However, it is important to recall that only four different
nucleotides constitute the basic building blocks of
DNA. Then, we have recourse to accurate nucleotide
structures as a departure point to create arbitrary
DNA sequences.
In a previous investigation, the geometries of
nucleic acid bases and these of their pair complexes
were determined w10x. The method under use was a
density functional approach which in particular has
shown to give reliable results for these kind of
compounds w11x. Hence, by making use of the same
scheme the structures of the B-DNA nucleotides:
adenine ŽA., guanine ŽG., cytosine ŽC. and thymine
ŽT., were obtained w12x. From such structures, we
now face the possibility of building single and even
double strand sequences of B-DNA.
The process to create the chain from its basic
components essentially follows the next steps. We
first proceed to overlap the sugar rings of all nucleotides. This is a process that becomes possible as
the sugar ring represents a common structure to all
monomeric units. Next, we locate nucleotide structures in such a way that nucleic acids lie in the Z s 0
plane, without loosing the previous overlap among
sugar rings. This is also an event that becomes
possible since nucleic acids are to great extent planar. In order to find the position of the helix origin,
we put in a stacking configuration a couple of nucleotides. The position of the origin is found out by
matching the location of the phosphate oxygen with
R. Santamaria et al.r Chemical Physics 227 (1998) 317–329
largest Z-component of the first nucleotide, with the
oxygen that links the sugar ring of the second one.
The matching process requires of the fact that ten
B-DNA bases yield a complete helix turn, and therefore the twist angle between bases is ; 368 w13x.
From this step we obtain an average helix rise per
˚ We note that such a value falls inside
base of 3.0 A.
˚ w13x. Once
the experimental range of 3.36 " 0.42 A
the rise per base along the Z-direction and the twist
angle around the helix axis are known, the desired
sequence of nucleotides in a single strand conformation can be built up by repeating the above steps 1.
Complementary nucleotides to these which appear
in the single strand, in order to form a double helix,
may be produced by transforming the Cartesian coordinates Ž x, y, z . of the partner nucleotide to the
coordinates Ž x, yy, yz .. With the use of the nucleic
acid pair complexes w10x as coupling molecules, it is
possible to build the entire complementary strand,
thereby forming the required double helix of B-DNA
nucleotides.
Local variations in the helix geometry are possible by allowing subtle changes on parameters, as for
example; the rise per base, twist angle between
nucleotides, propeller twist angle between bases, etc.
w14x. Also, it is important to note that, since the helix
chain was not allowed for an energetic relaxation,
the resulting structure represents a first approximation to the true helix in the gas phase. Nevertheless,
the DNA molecule is a dynamic entity which preserves its identity under certain limits and, as a
result, our approximate B-DNA structure should to
good extent retain the important electronic features
of the true system. To our best knowledge, this is the
first B-DNA structure whose monomeric species are
obtained from all-electron self-consistent-field calculations.
Finally, in this work we focus attention on nucleotides in a single strand configuration and in the
usual direction recognized as 5X ™ 3X . In fact, we
limit our analysis to doublets, considered as the
shortest sequences, since we are interested on charge
1
In addition to the nucleotide coordinates of Ref. w12x, bonds of
terminal oxygens, linked to the deoxyribose ring, were saturated
with hydrogen in order to simulate continuation of the helix chain.
In Fig. 3 such a hydrogen appears under notation H15.
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distribution changes of nucleic bases when these are
incorporated into nucleotides in a stacking geometry.
We resort to density functional theory ŽDFT. to
perform all computations. It is understood that DFT
is one of the most flexible and reliable quantum
mechanical techniques, appropriate for the relative
large size compounds studied here, since simpler
methods unfortunately fail on accuracy, while higher
accurate schemes demand for time-consuming computations w15x. Hence DFT seems to be the suitable
approach to study reactivity. In particular the method
is based on the use of the wave function as traditional quantum mechanical methods do, and on the
electron density. Both variables play a major role for
solving self-consistently Schrodinger-type
monoelec¨
tronic equations that emerge in the theory, and represent key ingredients for evaluating relevant quantities, among which MEPs and Mulliken population
charges are of our concern. Further details about the
application of the DFT approximation to DNA fragments are available from previous works w10–12x,
and details about the method itself from literature
w16–18x.
3. Mulliken charge populations and molecular
electrostatic potentials
3.1. The case of the nucleic acid bases and their pair
complexes
We show Mulliken populations of the nucleic acid
bases in Fig. 1. It is found that all nitrogens and
oxygens accumulate negative charge as a result of
molecular relaxation. The excess is taken from nearby
hydrogens and carbons which appear with positive
sign. Negative populations around those nitrogens
and oxygens with no hydrogen link promote the
formation of deep electrostatic potential wells in the
neighborhood, thus pointing out chemical active sites
Žalso depicted at Fig. 1..
For the case of purine ŽA and G. molecules we
find 3 electrostatic potentials wells, while for the
case of pyrimidine ŽT and C. species only 2 are
located. Their minima are reported in Table 1. Cytosine and guanine yield the deepest minima in comparison with their counterparts thymine and adenine.
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Fig. 1. Mulliken charge populations and molecular electrostatic potentials of DNA nucleic acid bases. Small rings identify minima in the
electrostatic potential surfaces.
Therefore, the G and C fragments yield the highest
probabilities for interaction with alkylating agents or
for an electrophilic attack. Our results are in good
agreement with those of Ref. w3x, except for cytosine.
According to that reference, nitrogen N3 of cytosine
renders a value of y93.5 kcalrmol, apparently more
negative than O8 of the same molecule by just 6.8
kcalrmol. A result that, under the own words of its
authors, is rather remarkable.
The number, location and shape of reactive sites
associated to nucleic acids represent important electronic features, in addition to geometric factors, that
R. Santamaria et al.r Chemical Physics 227 (1998) 317–329
321
Table 1
Minima of molecular electrostatic potentials ŽMEPs. for the case of DNA nucleic acids a, b
Center
MEP Žbase.
MEP Žbaserpair.
MEP Žbaserdinucletide.
08
N7
O10
N3
N3
N1
N7
O8
O7
N3
70 ŽC.
66 ŽG.
61 ŽG.
60 ŽC.
52 ŽA.
51 ŽA.
49 ŽA.
47 ŽT.
42 ŽT.
37 ŽG.
39 ŽCrCG.
72 ŽGrCG.
63 ŽGrCG.
155.5 " 8.5 ŽCrAC, CG, CT, CC, CC.
163 " 2 ŽGrAG, CG.
144 " 2 ŽGrAG, CG.
153.5 " 6.5ŽCrAC, CG, CT, CC, CC.
135.5 " 5.5 ŽArAT, AG, AC.
140 " 4 ŽArAT, AG, AC.
156.5 " 3.5 ŽArAT, AG, AC.
134 " 1 ŽTrAT, CT.
149 " 0 ŽTrAT, CT.
136.5 " 0.5 ŽGrAG, CG.
51 ŽArAT.
44 ŽArAT.
40 ŽTrAT.
45 ŽTrAT.
48 ŽGrGC.
a
All minima, in ykcalrmol, are found at the planes of nucleic acid bases.
Abbreviations: A s adenine; C s cytosine; G s guanine; T s thymine. For pairs ArAT, for example, denotes adenine in the Watson–Crick
pair AT, while for dinucleotides, it denotes adenine in the dinucleotide AT with T above A as depicted in Fig. 3.
b
must be taken into account in order to infer the kind
of compounds that NABs may interact with w7x. As
an example, let us consider the case of guanine and
cytosine. Both molecules contain the type of nitrogens and oxygens responsible for the presence of
potential wells, then we can visualize such atoms as
acceptor-like elements. On the other hand, hydrogens
are recognized as donor-type entities with opposite
sign. Hence, formation of different hydrogen bridges
between G and C becomes possible due to the
presence of donor and acceptor species in both fragments. As a result, different dimer residues are expected to appear, among which the Watson–Crick
pair ŽFig. 2. represents a particular situation.
Table 2 gives all feasible forms of H-bonded pairs
among the NABs. The different conformers are described according to the donor and acceptor atoms
taking part in the binding. In all these structures at
least two hydrogen links appear 2 , and in most cases
donor atoms from one fragment fall deep inside the
potential wells created by the acceptor atoms of the
partner molecule.
Experimental evidence about the occurrence of
these H-bonded pairs in vacuo has so far been
missing. However, in solution, pair formation of
nucleic acid bases can be indirectly inferred. Nucleic
2
In general, pairs with only one hydrogen bridge are energetically less stable than those which contain two or more bridges.
Thus, in this work, a H-bonded complex should be understood as
containing two or more H-links.
residues immersed in a non-aqueous medium tend to
pair with higher rate than these in an aqueous solution. In the latter case water molecules come into
competition to produce H-bonded compounds, leading to lower association constants among NABs that
show on enthalpy changes. Nevertheless, problems
arise when one tries to elucidate the kind of microscopic conformation adopted by dimers. A direct
way to obtain structural information is by forming
crystalline complexes among the different derivatives of the NABs, and performing the corresponding
X-ray diffraction analysis. Henceforth, when one
compares results from experiment with these predicted from Table 2, it is found that most of them
indeed crystallize in a diversity of arrangements w19x.
Observations under this scheme show that nucleic
acid bases are capable of linking with themselves
producing homologous pairs, or with other bases
resulting in mixed complexes where two, three or
more NAB derivatives coexist in the H-bonded infinite network. Water molecules, and either tautomeric
species of NABs, may also engage in the binding to
give rise to alternative crystallographic forms. Interestingly enough is the fact that contrary to NABs
immersed in solution, in crystals, Watson–Crick
linkages among the different nucleic acid derivatives
seem to be energetically less stable than other types
of H-bonding. Differences in their stability are attributed to different environments.
For the particular case of Watson–Crick pair
complexes in vacuo, we have also carried out a
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R. Santamaria et al.r Chemical Physics 227 (1998) 317–329
Table 2
Different pairs of acceptor and donor atoms for each nucleic acid
base a, b, c
Adenine
Guanine
Thymine
Cytosine
N1, H12
N1, H13
N3, H13
N3, H15
N7, H11
N3, H13
N3, H16
N7, H15
O10, H14
O7, H13
O7, H14
O8, H10
O8, H14
N3, H9
O8, H13
a
As a matter of example, adenine is capable of producing two
hydrogen bridges with cytosine if atoms N1 and H12 of A link
with atoms H9 and N3 of C, respectively.
b
In particular, the AT Watson–Crick pair corresponds to the
binding of the set N1, H12 of adenine with the set O8, H14 of
thymine. For the GC Watson–Crick pair, the corresponding sets
are O10, H14 of guanine and N3, H9 of cytosine. The extra
hydrogen bridge in the GC pair is implicitly contemplated in this
binding since two links are enough to determine the kind of pair
conformation.
c
Take note that, in addition to mixed dimers, homologous pairs
should be also contemplated from the table.
Mulliken analysis. Similar charge population results
to these reported for single residues are found, refer
to Fig. 2. No Mulliken charge transfer is noted from
one molecule to the other since each fragment that
builds the complex essentially retains its zero initial
charge. However, substantial electronic reorganization occurs within each nucleic acid at the interaction
region. If we compare Mulliken charges of those
atoms taking part in the binding, before and after the
formation of the complex, it is observed that hydrogens increase their positive charge while nitrogens
and oxygens increase their negative charge. The new
electron distribution induces local charge polarization between the partner molecules forming the
dimer. It calls our attention that carbons 2, 5 and 6 of
adenine, 4 of thymine, 5 and 6 of guanine, and 2 and
4 of cytosine also exhibit considerable charge readjustment, even when they are located relatively far
away from the binding region.
MEPs for the Watson–Crick nucleic complexes
are likewise depicted in Fig. 2. In pair complexes
some of the original electrostatic potential wells
attached to single NABs disappear. For instance, a
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total of 3 wells are found for single adenine before
forming the complex, and only 2 of them are left
once the formation of the AT dimer has taken place.
The main reason is the near presence of atom H14 of
thymine which produces a hydrogen bridge with N1
of adenine. Equivalent results about the lost of binding sites are observed for complex GC, where the
formation of hydrogen bridges N3–H14 and O8–H12
essentially eliminates two potential wells initially
attached to atoms N3 and O8 of cytosine. On the
other hand, electrostatic potential wells that survive
in the process of dimer formation largely preserve
their original shape, and only some of them are cut
or confined within a shorter region. Such potential
wells in turn become the characteristic reactive centers of the Watson–Crick pair complexes.
The lowest values of the electrostatic potential
surfaces corresponding to the AT and GC compounds are shown in Table 1. In comparison with
single nucleic acids, the relative order among minima is greatly modified by pair formation. For example, the most drastic change is recorded for site O8
of cytosine. In the case of pairs, active site O8 shows
the shallowest minimum, contrary to the case of
single nucleic acids where it represents the deepest
one.
For other pair conformations among NABs, with
equal demand of time-consuming computations, similar results are expected. In fact, Watson–Crick
dimers represent just an example where chemical
active centers of single nucleic acids are potentially
capable of linking a molecular partner in different
conformations. Still, the question remains about possible changes of MEPs and population charges of
NABs when other DNA constituents remain in their
vicinity, a topic to be investigated next.
3.2. The case of the B-DNA single strand
In this section we analyze charge populations and
electrostatic potentials when nucleotides Žnucleic acid
bases in conjunction with sugar and phosphate subunits. appear in a stacking configuration, or equiva-
Fig. 2. Mulliken charge populations and molecular electrostatic potentials of DNA pair complexes. Small rings identify minima in the
electrostatic potential surfaces. For comparison, charge populations of nucleic acids before pairing are also included.
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lently in a single strand conformation. This analysis
represents a more general study than previous studies
performed on single nucleic acids by other authors as
we now take into account the additional contributions of phosphate groups and sugar compounds.
Such contributions can not be neglected due to the
long range nature of the forces that participate in the
electrostatic potential expression.
On the other hand, because of the large size of the
DNA chain, we concentrate our study on the shortest
complexes, this is doublets of nucleotides. Sixteen
possible structures is the total number of compounds;
however, we only need analyze the four combinations between purines and pyrimidines to determine
electron distribution changes. Hence, we choose pairs
AT, AG, CT and CG as examples. Figs. 3 and 4
illustrate the AT and AG doublets and establish atom
numbering.
We first pay attention to sugar and phosphate
subunits and later on to the nucleic acids themselves.
Careful comparisons of Mulliken populations among
corresponding atoms, taking part in sugars and phosphates of the above mini-strands, indicate small differences. In Fig. 5, plots of Mulliken net charges
versus atom label are shown. Only three curves are
depicted there since all remaining data fall on one of
such curves. It is not difficult to see that the largest
discrepancies in sugar compounds are recorded for
atoms C3, C4, O6 and H9, while for phosphate
fragments differences appear at oxygens O3, O4 and
O5. The deviations are indeed small and, in most
instances, curves follow a similar trend. Changes
computed on atoms C3, C4 and H9 of sugar
molecules are attributed to a poor influence of the
adjacent nucleic bases that participate in the doublet,
while these changes recalled on oxygens are mainly
due to the location of the phosphate molecule. The
phosphate may stay in between or at the end of the
strand, leading to different kinds of binding which in
turn originate different atomic charges because of the
finite size of the chain. In spite of that, atomic
population discrepancies in sugar compounds and
Fig. 3. Molecular electrostatic potentials, at the planes of nucleic acids, for the DNA sequence AT. Dark and transparent surfaces belong to
A and T, respectively. Small rings identify relative minima and strips gaps of 10 kcalrmol, starting from 120 downwards, in the
electrostatic potential surfaces. Refer to Fig. 1 for atom numbering in the nucleic acid bases.
R. Santamaria et al.r Chemical Physics 227 (1998) 317–329
325
Fig. 4. Molecular electrostatic potentials, at the planes of nucleic acids, for the DNA sequence AG. Dark and transparent surfaces belong to
A and G, respectively. Small rings identify relative minima and strips gaps of 10 kcalrmol, starting from 120 au downwards, in the
electrostatic potential surfaces. Refer to Figs. 1 and 3 for atom numbering in the nucleic acid bases, sugar and phosphate compounds.
phosphate groups in general appear negligible enough
that, it is our opinion, they are incapable of producing decisive changes on reactivity. Such an argument
is based on the fact that DNA assumes a dynamical
role in a variety of biochemical processes. Therefore,
the flexibility of DNA is one of the main reasons
that such a molecule is capable of preserving, even
under different conformations, the important genetic
code. However, take note that it may be equally
valid the conclusion that the observed differences in
population charges of sugar and phosphates are important enough that such subunits can be considered
as the first recognition sites to discriminate among
the attached nucleic acid bases w20–22x. Nevertheless, we remark and insist on the molecular flexibility of DNA to preserve the genetic information under
relatively wide structural and electronic limits. Consequently, we may say that sugar and phosphate
molecular groups preserve their electronic identity
within some margins and constitute not only a struc-
tural, but also a common electronic backbone of
DNA according to a Mulliken population analysis.
Mulliken population comparisons have been also
carried out for nucleic acid bases in the four possible
single strands. We find that charge populations of A
in the sequence AG are almost identical to these of
A in AT, see Fig. 6. The same situation is observed
for G in AG and CG, for T in AT and CT, and for C
in CG and CT. Then, within the doublet approximation, Mulliken charges of nucleic bases are indifferent to the contiguous base, whether this last one is
situated above or under the reference nucleic acid.
As a matter of fact, major charge population changes
in nucleic bases are produced by the near presence of
sugar and phosphate compounds. For instance, adenine alone and within the mini-strands shows substantially different charge populations, refer to Fig.
6. Equivalent results occur for the other bases. The
new charge distribution of nucleic bases in the ministrands is mainly perceived at their junction with the
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Fig. 5. Mulliken populations of the eight sugar and phosphate subunits taking part in the mini-sequences AG, AT, CG and CT. Only three
curves are shown since all data fall in one of such curves: sugar and phosphate of adenine in AG Ž –v – ., of guanine in CG Ž –B– . and of
thymine in AT Ž –'– .. Refer to Fig. 3 for atom numbering in sugar and phosphate groups.
sugar molecule Žsee, e.g., N9 in Fig. 6. and in the
case of purines, the redistribution includes the sixmembered rings.
On the other hand, MEPs of A inside the sequences AT and AG are depicted at Figs. 3 and 4. In
these figures, the two surfaces generated by the A
nucleotide show similar not only in shape, but also in
reference to the depth of potential wells. However,
this is not the case when we compare the adenine
surface with that generated by the G nucleotide.
Guanine with its phosphate group yield an extended
surface with just one isolated well Žin the vicinity of
N3. that simulates an island, see Fig. 4. In contrast,
adenine and its corresponding phosphate molecule
exhibit a less extended surface and two isolated
wells Žone near to N1 and the other near to N3.. On
the other hand, if we compare MEPs produced by
purines against these of pyrimidines, clear differences emerge. Pyrimidines present surfaces separated
from those of the phosphate group due to the inter-
position of H-bonds of either the amino group NH of
cytosine or radical CH of thymine, refer for instance
to Fig. 3. Hence, electrostatic potential wells of
pyrimidines, because of their relative small size,
become slightly more inaccessible within the DNA
complex. Still note that the external part of the
electrostatic potential surfaces produced by phosphate groups of purines and pyrimidines resemble
each other. In fact, main differences in MEPs of
dinucleotides are introduced by the nucleic acids
themselves. For larger single strands we expect similar results.
In Table 1, we consider the lowest values in the
MEP surface associated to nucleic acid bases. Six
different dinucleotide systems have been now contemplated there to carry out some statistics, namely;
AG, AT, AC, CG, CT and CC. Values appear with
deviations in order to summarize results in one central value and be able to establish relative order
among minima. In particular, we observe that chemi-
R. Santamaria et al.r Chemical Physics 227 (1998) 317–329
327
Fig. 6. Mulliken populations of adenine alone and in the mini-strands AG and AT. Refer to Fig. 1 for atom numbering.
cal active center N7 of guanine and adenine leads to
the deepest potential wells. They are closely followed by these produced by O8 and N3 of cytosine,
and O7 of thymine. Note also that the relative order
among minima in this last column differs from previous columns of Table 1. Therefore, preferred sites
for electrophilic attack of nucleic bases participating
in dinucleotides are different to these previously
predicted for single nucleic acids and base pairs.
However, as a common factor among values of
Table 1, all minima are found at the planes of
nucleic acid bases Žregardless the bases stay alone,
forming pairs or building dinucleotides.. Other authors w3x have found secondary minima out of the
planes of nucleic acids A and C. Nevertheless, a
careful DFT analysis indicates that it is due to the
nonplanarity of amino hydrogens. When nucleic
bases take part in base pairs, such hydrogens become
planar and the secondary minima disappear. In dinucleotides, minima out of the molecular plane are
observed for A in AG and AT, and for C in CG and
CT. The minima of A and C are located in opposite
direction to the other nucleotide building the dinucleotide, in this case G or T. For the interesting
mini-sequence AC, which involves both A and C, we
observe a minimum out of the plane of A but do not
observe a minimum out of the plane of C. A similar
situation occurs for C in C 1C 2 , where there is an out
of plane minimum attributed to the first cytosine
ŽC 1 . but not found in the second one ŽC 2 .. Hence,
the stacking conformation of nucleotides becomes an
important factor, in addition to the planarity of amino
hydrogens, to make disappear such kind of secondary minima.
Based on the above results of Mulliken charge
populations and MEP for phosphates, sugars and
nucleic acid bases, we conclude that recognition of
specific DNA sequences proceeds at short distances.
The assertion derives from the fact that Mulliken
charges and MEPs associated to phosphate and sugar
subunits keep to great part their own electronic
identity as a result of a relative poor influence from
adjacent nucleic acid bases. Therefore, a partner
molecule approaching to DNA is expected to be first
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attracted by the strong field created by the phosphate
group w23x and, as the partner gets closer, potential
wells of nucleic acid bases come into play in the
selective process favoring a close contact recognition. This result is experimentally evidenced in gene
regulatory proteins w24x.
Finally, our results should be useful to understand
processes related to genetic recognition, such as
DNA transcription, where discrimination of nucleotides plays an important role. Also, they should
be of help to build more realistic models about the
dynamics of DNA replication. In this last case we
call attention to the molecular machine approximation, where one might refer to a molecular machine
as an assembly of polymeric molecules with one of
them sliding over the other, in order to transport
some energy or certain type of mass. Note that the
transportation of mass may be also understood as the
transportation of information w25x. Of course, the
sliding Žor sticking. of molecules should depend on
the potential wells that one molecule finds along the
other one.
4. Conclusions
In this work we have shown the simplicity and
importance of molecular electrostatic potentials and
Mulliken charge populations to elucidate reactive
centers of DNA. The application of both schemes to
the nucleic acid bases revealed the existence of a
variety of H-bonded associates among NABs. Experiments based on their derivatives confirm the dominant role of the electrostatic force, that participates in
the MEPs, for predicting the pairing of compounds
of such nature. Particular attention given to
Watson–Crick dimers showed that, electronic charge
is mainly reaccommodated at the interaction region
between fragments, inducing local polarization, with
the consequent lost of some binding sites. Surviving
electrostatic potential wells in the process of dimer
formation remain essentially with the same shape,
except at some instances where they show clipped
sides.
A study on nucleotides indicated that sugar
molecules and phosphate groups represent not only a
structural, but also an electronic backbone of DNA.
Nucleic acid bases in dinucleotides do not show
important charge readjustment for the presence of a
contiguous base, weather this last one is positioned
above or under the reference nucleic acid. Then, it is
assumed that selective interactions between partner
molecules with DNA may be characterized as close
contact interactions since nucleic acids are uncapable
of substantially altering the charge populations and
molecular electrostatic potentials of sugar and phosphate subunits that could indicate the presence of
one or another adjacent nucleic acid base.
Nucleic acids taking part in dinucleotides yield
different preferred sites for an electrophilic attack to
these found in single nucleic acids and pair complexes. This is due to the additional contributions of
phosphate and sugar compounds, which are not negligible because of the long range nature of the electrostatic forces that appear in the MEP expression.
However, a common factor among all reactive centers is the fact that they appear with their lowest
values at the planes of nucleic acids, with some
secondary sites observed out of molecular planes
under special circumstances.
Finally, it is important to mention that, the set of
hydrogen atoms that participate in the binding of
nucleic acid bases not only ensures a weak linking
between bases, but also help to preserve the identity
of each base inside the DNA complex. This is due to
the limited charge reorganization that hydrogen atoms
can suffer in comparison with heavier elements that,
otherwise, could appear at the interaction region.
Features like weak bonding make possible the process of exact duplication, while electronic identity
preservation of nucleic acids in DNA makes possible
the saving and interpretation of the genetic information.
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