Computational and Theoretical Chemistry 1204 (2021) 113422

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Computational and Theoretical Chemistry

journal homepage: www.elsevier.com/locate/comptc

Intermolecular interactions in microhydrated ribonucleoside and

deoxyribonucleoside: A computational study
Venkataramanan Natarajan Sathiyamoorthy a, *, Ambigapathy Suvitha a, Ryoji Sahara b,
Yoshiyuki Kawazoe c, d, e
a
SHARP Substratum, Adavathur East, Trichy-620 102, India
b
Research Center for Structural Materials, NIMS, 1-2-1 Sengen, Tsukuba, Ibaraki 305-0047, Japan
c
New Industry Creation Hatchry Center (NICHE), 4-4-6 Aramaki aza Aoba, Aoba-ku, Sendai 980-8579, Japan
d
Department of Physics and Nanotechnology, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
e
School of Physics, Suranaree University of Technology, 111 University Avenue Muang, Nakhon Ratchasima 30000, Thailand

A R T I C L E I N F O A B S T R A C T

Keywords: The nature of interactions between the ribonucleoside and deoxyribonucleoside with water molecule was
DFT examined employing the dispersion corrected density functional theory and wave functional analysis. In the
AIM nucleosides, the water binds with the 5′ –OH hydrogen and N3 nitrogen or N7-H group. In the deoxynucleosides,
Electrostatic potentials
the water binds through 3′ –OH and N3 nitrogen or carbonyl oxygen. The interaction energy, binding energy,
Non-covalent interactions
hydration entropy and enthalpy do not show any appreciable change for the nucleoside-water complexes,
emulating the experimental findings. Electrostatic potential analysis shows that the most positive region is
observed near the 5′ –OH hydrogen atom of the ribose unit in nucleosides. In deoxynucleosides, the 3′ –OH
hydrogen has Vs,max values equivalent to 5′ –OH hydrogen atom. Hence, the water binds with the 3′ –OH hydrogen
and the nucleobase. QTAIM analysis shows the presence of medium-strength hydrogen bonds between water and
nucleoside. In deoxynucleoside-water complexes, in addition to the 3′ –OH hydrogen bonding with water, the
nearby 2′ C–H in ribose unit bonds with oxygen in the water molecule. QTAIM and EDA analysis show the
intermolecular bonds are noncovalent and electrostatic dominant. The 2D RDG plot shows, additional spikes due
to the interaction of 2′ C hydrogen with water oxygen. The 3D spatial diagram shows the existence of several
green patches in the deoxynucleoside-water complexes, associated with the weak van der Waal’s interactions
which make them more stable.

1. Introduction only a limited number of water molecules contribute significantly to the

The nucleosides and deoxynucleosides are a fundamental unit of the
RNA and DNA respectively in the human body [1–3]. The nucleosides
are glycosylamines containing a nucleobase (pyrimidine or purine)
attached to a carbohydrate ribose sugar via a beta-glycosidic linkage [4].
The purine bases present in RNA are adenosine (A) and guanosine (G),
while the pyrimidine-based nucleosides are cytidine (C) and uridine (U).
While in the DNA purine-based deoxyadenosine (dA) and deoxy­
guanosine (dG) were present along with the pyrimidine-based deoxy­
thymidine (dT) and deoxycytidine (dC) [5]. The biological function and
structure of DNA and RNA are strongly pretentious by the interactions of
the nucleobases with an aqueous environment composed of water and
solvated metal ions [6]. This environment is generally microcosmic and
modulation of the three-dimensional structure of DNA [7,8]. The
numbering sequence for the nucleoside and deoxynucleosides are pro­
vided in the supporting information as Scheme 1. Furthermore, the
conformational rigidity of RNA comparative to DNA is often elucidated
by additional hydration to the 2′ -OH group of ribose [9].
Despite the above facts, the nucleosides appear today to have great
biological importance as antibacterial, antiviral, anti-carcinogenic,
antiprotozoal, and antithyroid drugs [10–15]. Contrariwise, water sol­
ubility is a significant molecular property for effective drug develop­
ment, as it is a crucial factor governing drug access to biological
membranes. Hence, theoretical investigations with explicit interaction
between the biomolecule and a few water molecules in the gas phase are
of paramount importance, even though the major chunks of the

* Corresponding author.
E-mail address: nsvenkataramanan@gmail.com (V. Natarajan Sathiyamoorthy).

https://doi.org/10.1016/j.comptc.2021.113422
Received 8 June 2021; Received in revised form 4 August 2021; Accepted 16 August 2021
Available online 20 August 2021
2210-271X/© 2021 Elsevier B.V. All rights reserved.
V. Natarajan Sathiyamoorthy et al.
experimental works are carried out in condensed phases [16–18].
Furthermore, experiments on isolated nucleosides and nucleotides show
that the biomolecules undergo conformational change during micro­
hydration [19–21]. Understanding the hydration of biomolecules at the
microscopic level in their correct composition and conformation, such
that they exist in the biochemical process is vital to understand the
process associated with them.
In past theoretically and experimentally, isolated nucleic acid bases
were studied with explicit water molecules in their first solvation shell,
which has established that the electronic structure and the tautomeri­
zation of nucleobases are influenced by the water molecules [22 –26].
While isolated nucleobases have been studied extensively, less is known
about nucleosides, due to their low stability under gas-phase experi­
mental conditions. Studies to understand the configuration of guano­
sine, and deoxyguanosine were carried out experimentally and
theoretically [27–30]. The nucleoside and deoxynucleosides were found
to occur in syn and anti conformers. The syn conformer is stabilized by
the intramolecular hydrogen bonding between the N3 site of the base
and the 5′ –OH group of sugar units [31]. While the chemically modified
5-O-ethylguanosine prefers an anti-conformer due to the involvement of
the 2′ –OH group [32]. Recently, Rodger and co-workers, have shown by
infrared multiple photon dissociation (IRMPD) action spectroscopy, the
protonated 2′ -deoxyguanosine and guanosine to adopt anti conforma­
tions and the protonation occurs at the N7 site [33]. On the contrary, 2′ -
deoxyadenosine and adenosine were found to present in syn conforma­
tion [34].
Wincel calculated the thermodynamical parameters for the hydra­
tion of protonated nucleosides using an electrospray high-pressure mass
spectrometer coupled with a pulsed ion-beam reaction chamber [35].
The entropy values were found to be more negative and only little
variation in the hydration enthalpy was observed among nucleobase/
nucleosides. Saigusa and coworkers, studied the IR spectra of mono and
dehydrated guanosine and 2′ -deoxyguanosine clusters using IR-UV
double resonance spectroscopy [36,37]. They notice the hydration oc­
curs at the 5′ –OH group of the sugar and the amino group of the guanine
moiety and the absence of the 2′ –OH group does not influence the
monohydrated structure. Furthermore, the ionized adenosine dimers
obtained in resonant two-photon ionization and detected by time-of-
flight mass spectrometer show that a stacked structure is stabilized by
the formation of a hydrogen-bonding network involving the two sugar
groups [38]. Very recently, Ding and co-workers studied the micro­
hydration of neutral and charged cytidine and uridine and noticed that
adiabatic electron affinities increase linearly with the number of water
molecules [39,40]. The reduced density gradient (RDG) isosurfaces
show the presence of hydrogen bond, van der Waals, and steric effect
between water and cytidine nucleoside.
Herein we report the hydration of nucleosides and deoxynucleosides
using the density functional theory. The main discussion on the paper
will be focused on (i) addressing the water binding site with nucleoside
and deoxynucleoside (ii) how are the stability and thermodynamic pa­
rameters vary for the hydration process with the nucleoside and deox­
ynucleosides (iii) what are the forces that are responsible for the site of
binding of water molecules (iv) what is the effect of ribose group on the
hydration of nucleobases. To address, the above issue, we first identified
the lowest energy conformer. On the lowest energy conformer, the na­
ture of the interaction was analyzed by performing a combined quan­
titative molecular electrostatic potential (MESP), atoms-in-molecules
(AIM) analysis, and energy decomposition analysis (EDA). The non-
covalent interactions in the complexes are unraveled using the non­
covalent interaction-reduced density gradient (NCI-RDG) analysis.
Finally, we have compared the present results with the nucleobase-
water complex to know the role of ribose in nucleoside and
deoxynucleoside.
2
Computational and Theoretical Chemistry 1204 (2021) 113422
2. Computational details
All the density functional theory calculations were carried out using
the Gaussian 16 (Revision C.01), a suite of programs [41]. The optimi­
zation of structures was carried without any symmetry constraints using
the M06-2X/6–311 + G(d,p) method, with Grimme’s D3 dispersion
correction [42]. According to previous studies, M06-2X functional pro­
vides reasonably accurate bonding energies especially for stacked uri­
dine dimers and is highly parameterized to yield high accuracy for main
group thermochemistry and noncovalent interactions [43,44]. To
confirm that the optimized structures are in the real minima and not the
saddle points, vibration analysis was done using M06-2X-D3/6–311 + G
(d,p) method and the absence of imaginary frequencies demonstrates
that the stationary points are real minima. Energies are evaluated on the
optimized geometry using the M06-2X/6–311 + G(d,p) method. The
binding energy of the water molecule is computed using equation (1)
ΔEBSSE
binding = E(B.H2 O) − (E(B) + E(H2 O) ) + EBSSE (1)
In the above equation,ΔEBSSE binding is the binding energy of the water
molecule corrected for basis set superposition error (BSSE). E(B⋅H2O) is
the total electronic energy of the nucleoside/deoxynucleoside water
complex, E(H2O) is the total electronic energy of the water molecule,
and EBSSE the basis set superposition energy obtained in the counterpoise
correction. To arrive at the BSSE correction values, we used Boys and
Bernardi’s counterpoise method [45]. The deformation energy is ob­
tained by the difference in energy between the single point energy of the
component in the optimized hydrated complex using equations (2) and
(3)
( )
ENuOPT
SP
Edef (Nu/deoxynu) = ENu/deoxynu − (2)
deoxynu
( )
Edef − (H2 O) = EHSP2 O − EHSP2 O (3)
where Edef-(Nu/deoxynu) is the deformation energy of the nucleoside or
deoxynucleoside, Edef-(H2O) is the deformation energy of the water
molecule, ESP
Nu/deoxynu and EH2O are the single point energies of the struc­
SP
ture of nucleoside or deoxynucleoside and the water molecule is taken
from the optimized hydrated complex. EOPT
Nu/deoxynu and EH2O are the en­
OPT
ergies of free nucleoside or deoxynucleoside and water molecules in
their most stable geometries.
The interaction energy (Eint) of the water molecule is computed using
equation (4).
( )
OPT
Eint = ENu/deoxynu SP
− ENu/deoxynu + EHOPT (4)
2O
To understand the main intermolecular interactions that stabilizes
the nucleoside and deoxynucleoside-water complex and to tag their
nature and strength, we used quantitative molecular electrostatic po­
tential analysis (MESP), natural bond orbital (NBO), quantum theory of
atoms in molecules (QTAIM) analysis, energy decomposition (EDA), and
noncovalent interaction analysis – Reduced density gradient (NCI-RDG)
analysis. The basic background of MESP [46–49], AIM [50] and NCI-
RDG [51] analysis can be found in the previous literatures. The
QTAIM analysis has been performed using AIMALL package [52], and
the corresponding wave functions were generated at the M06-2X-D3/
6–311 + G(d,p) level of theory. The NCI-RDG analysis was carried out
using the Multiwfn program [53]. The visualization of the gradient
isosurface in real space was made using the Chemcraft program [54].
The energy decomposition analysis (EDA) is carried out at the M06-2X-
D3/TZ2P level using ADF(2018) program package [55].
V. Natarajan Sathiyamoorthy et al.
3. Results and discussions
3.1. Structure of nucleoside-water and deoxynucleoside-water complexes
The optimized geometries of nucleoside and deoxynucleoside are
used as the starting point to apprehend the various nucleoside and
deoxynucleoside-water complexes. Although nucleoside and deoxy­
nucleoside can exist in syn- and anti-configuration, anti has been
considered in the study as it plays a vital role in the formation of DNA
double helix structures [36,37]. The optimized geometries of nucleo­
sides and deoxynucleosides are provided in supporting information
Figure S1. The water molecule is placed around the nucleoside and
deoxynucleosides with the lowest contact distance of ≤ 1.0 Å and with
an utmost distance of ≥ 4.0 Å. This distance is considered as the strong
and weak hydrogen bonding distance between water and the substrate
in most hydrated systems [56,57]. While introducing the water mole­
cule, we considered all the possible water binding sites and hydrogen
bonding forces that can exist between the nucleoside, deoxynucleoside,
and water. In our previous study, we have used the above strategy to
identify the stable nucleobases-water complexes [17]. Furthermore,
previous studies on hydrated uridine and cytidine were also considered
as a guide for various initial geometries [39,40]. In Fig. 1, we depict the
most stable geometries of nucleoside, deoxynucleoside with a water
molecule, and list them with the intramolecular hydrogen bond length.
The structures of five to seven low lying isomers arranged in the order of
decreasing stability are provided in supporting information Figure S2
and S3 (ESI) for nucleosides and deoxynucleosides respectively.
In the most stable structure of adenosine-water (A-H2O) and
guanosine-water (G-H2O), the water molecule binds through the N7
nitrogen atom of the five-member ring and the 5′ –OH group in the ribose
unit, thus coupling with both the purine base and the sugar moiety.
However, the bond length between water and the purine base was found
to vary. In the case of A-H2O, the bond distance between OW⋅⋅⋅H-O5′ was
1.859 Å and in G-H2O the bond length was 1.845 Å (See Figure S1 for
atom labeling). The OW-H⋅⋅⋅N3 was 2.072 and 2.023 Å in A-H2O and G-
H2O respectively. The small bond variation could be due to the modu­
lation in the electronic nature owing to the introduction of an amino-
functional group in the G-H2O complex. In the deoxyadenosine-water
(dA-H2O) complex, the water binds to the N3 nitrogen atom and the
3′ –OH group, while in the deoxyguanosine-water (dG-H2O) complexes,
Fig. 1. The most stable geometries for the nucleosides and deoxynucleosides with water molecule along with selective intermolecular distances (a-e) are for
nucleosides-water complexes, and (e-i) are for deoxynucleosides-water complexes.
3
Computational and Theoretical Chemistry 1204 (2021) 113422
the water binds through N7 nitrogen atom and 5′ –OH group in the ribose
unit via OW-H⋅⋅⋅N3 and OW⋅⋅⋅H-O5′ . In the dG-H2O, the structure with
water binding to the N3 –OH atom and the 3′ –OH group is 3.27 Kcal
mol− 1 less stable than the most stable complex.
In the cases of microhydrated pyrimidine-based nucleosides,
excluding the cytidine-H2O (C-H2O) complex, in thymidine-H2O (T-
H2O), and uridine-H2O (U-H2O), the water molecule is linked by the
carbonyl oxygen atom O8 and the N3-H hydrogen atom of the pyrimi­
dine base via OW⋅⋅⋅O = C4 and OW⋅⋅⋅H-N3. In the C-H2O, the water
molecule is bonded with cytidine through the N3 nitrogen and the N7-H
is linked to the C4 carbon. This binding site observed in the present
study matches with the recently reported minimum energy structure for
the C-H2O, computed using the B3LYP/6-311G(2d,2p) method [39,40].
The intermolecular bond length of T-H2O and U-H2O shows a very
minimal change due to the similar skeleton structure of the pyrimidine
bases. In the microhydrated pyrimidine deoxynucleosides namely
deoxycytidine-H2O (dC-H2O), deoxythymidine-H2O (dT-H2O), and
deoxyuridine-H2O (dU-H2O), the water molecule binds with the py­
rimidine bases through and the 3′ –OH group in the sugar moiety and the
carbonyl oxygen attached to the C2 carbon. The observed OW⋅⋅⋅H-O3′
intermolecular distance between the nucleoside and water was 1.822 Å.
This distance in dT-H2O and dU-H2O were 1.899 and 1.906 Å respec­
tively. It is evident from the above inference, the introduction of electron
releasing group to the uridine leads to the increase in OW⋅⋅⋅H-O3′ bond
length in dC-H2O and dT-H2O complexes.
In order to understand the quality of the chosen theoretical method
in the predicting the ground state geometry of the nucleoside-water and
deoxynucleoside water complexes, we have optimized the geometries of
the most stable and the low-lying isomers using various density func­
tionals (pure GGA: BP86, meta GGA: M06L, hybrid meta GGA: M062X
and the popular hybrid functional B3LYP-D3). All the functionals were
able to correctly predict the most stable geometry, which provides
confidence for us on the reported stable geometry using the dispersion
corrected M062X-D3 functional. However, we observed a change in the
order of low-lying geometries. In the case of U-H2O, the use of pure
functional BP86 shows isoenergetic for the most stable geometry and the
first low-lying isomer. Besides, in case of deoxynucleoside-water com­
plexes while using DF’s without dispersion some of the low-lying ge­
ometries were found to converge to the neighboring geometries, which
demonstrates the importance of dispersion correction in the
V. Natarajan Sathiyamoorthy et al. Computational and Theoretical Chemistry 1204 (2021) 113422

calculations.

Selected physical properties of the minimum energy geometries of nucleoside- H2O and Deoxynucleoside-H2O complexes obtained at M06-2X-D3/6–311 + G(d,p) method. The properties include average intermolecular
–O⋅⋅⋅H, N⋅⋅⋅H, N–H⋅⋅⋅H, O–H⋅⋅⋅H bonds distance between the donor and acceptor for water complexes (in Å), the deformation energy (inkcal/mol) on the nucleoside, deoxynucleoside, water, binding energy of water

17.22
16.77
18.41
16.61
16.41
3.2. Energetics and thermochemistry

Eint

−
−
−
−
−
Interaction energies calculated at the M06-2X-D3/6–311 + G(d,p)

binding

12.79
13.93
15.17
12.92
12.75
level for all the stable nucleoside and deoxynucleoside-water complexes

ΔEBSSE
are provided in Table 1. Presented data clearly show negative interac­

−
−
−
−
−
tion energies for all the stable complexes, which indicates their forma­
tion is feasible. Comparison of interaction energies among the

0.26
0.18
0.22
0.15
0.14
nucleoside-water complexes shows decreasing tendency in the order

H2O
A-H2O > G-H2O > C-H2O > U-H2O > T-H2O. In the case of
deoxynucleoside-water complexes, the decreasing tendency is in the
order A-H2O > G-H2O > C-H2O > T-H2O > U-H2O. The interaction

DNu

3.03
1.34
1.85
2.40
2.43
Edef
energies are higher for deoxynucleoside-water complexes as they can
undergo higher deformation during the complexation because of the
absence of the 2′ –OH group. To verify the above hypothesis, we

–O⋅⋅⋅H
computed the deformation energy of the nucleoside and deoxynucleo­

1.822
1.899
1.906
C–
side and the water molecule. It is evident from Table 1, that deoxy­

–
–
nucleosides have nearly double the deformation energies than the
nucleosides. Besides, the water molecule’s deformation energies are

1.961
1.988
N⋅⋅⋅H
Bond distance (in Å)
very similar in both complexes. These suggest that deoxynucleosides

–
–
–
have a higher tendency to undergo structural changes to afford a better
binding with the substrates.
To identify the relative stability of the nucleoside and

O–H⋅⋅⋅H
deoxynucleoside-water complexes, we computed the binding energies of

2.002
1.843
1.935
1.976
1.975
the stable complexes. The BSSE corrected binding energies for nucleo­
side and deoxynucleoside-water complexes, are provided in Table 1.
Among the binding energies of nucleoside-water, the A-H2O complex

DNu-H2O
has the highest interaction energy. The binding energy for nucleoside-
water varies only a little and lines in the range of − 13.98–− 10.42

dU
dG
dA

dC
dT
kcal mol− 1. The estimated binding energies follow the order G-H2O > A-
H2O > C-H2O > U-H2O > T-H2O, while the deoxynucleoside-water
complex has the order C-H2O > G-H2O > T-H2O > A-H2O > U-H2O.

− 14.58
− 16.25
− 13.63
− 11.79
11.85
The binding energy for deoxynucleoside-water varies in the range of

Eint
− 15.17–− 12.75 kcal mol− 1. Comparison between the binding energies
of nucleoside and deoxynucleoside-water complexes suggest that for
purine bases nucleoside-water complexes are more stable, while in the
binding

13.54
13.98
12.24
10.42
10.49
ΔEBSSE

pyrimidine bases the deoxynucleoside-water complexes to be more −

−
−
−
−
stable than their counterparts.
The binding energy of the complexes computed by BP86, B3LYP-D3,
M06-2X, M06L and M06-2X-D3 are summarized and compared in
0.14
0.16
0.23
0.18
0.18
H2O

Table 2. The widely used hybrid B3LYP functional with D3 dispersion

correction and the pure BP86 functional provides higher binding energy
for nucleoside-water complexes compared to the M06-2X-D3 functional.
0.95
0.80
0.29
0.30
0.31
Edef
Nu

Similarly, the meta GGA functional M06L, predicts the stability of

nucleoside-water complexes closer to the M062X-D3 functional values.
While in the case of deoxynucleosides, most of the functionals provides
inkcal/mol)and its interaction energies (Eint inkcal/mol).

N–H⋅⋅⋅O

lower stability for the complexes. A comparison between functionals

1.973
1.946
1.941

M06-2X-D3 and M06-2X with and without dispersion correction, clearly

–
–

show that dispersion terms improve the stability of the complexes. Thus
B3LYP-D3 functional, was found to perform significantly with lower
–O⋅⋅⋅H

performance, while the dispersion interactions contribute significantly

1.941
1.930
1.935

to the stability of the water complexes.

C–

–
–

To deduce the complexation ability of these water molecules with the

nucleoside and deoxynucleoside, we have computed the thermodynamic
parameters viz., standard free energy changes (ΔG◦ ), enthalpy changes
2.072
2.023
N⋅⋅⋅H
Bond distance (in Å)

(ΔH◦ ) and the entropy (ΔS◦ ) changes for the formation of these com­
–
–
–

plexes. Table 3 summarizes the thermodynamic parameters for the

complexes computed at 1 atm and 298.15 K using the partition functions
O–H⋅⋅⋅H

derived from the vibrational frequency calculations. Recently, Wincel

1.859
1.845

has reported the thermochemical data for the hydration of protonated

–
–
–

nucleosides measured using an electrospray high-pressure mass spec­

trometer equipped with a pulsed ion-beam reaction chamber [35]. The
hydration enthalpies for protonated uridine and thymidine were
Nu- H2O
(ΔEbinding
Table 1

BSSE

− 12.3–− 11.7 kcal/mol, while the entropy values were − 20.0 and 22.3
C–

U
G
A

C
T

kcal/mol K respectively. The reported Gibbs free energy for the

4
V. Natarajan Sathiyamoorthy et al. Computational and Theoretical Chemistry 1204 (2021) 113422

Table 2 moieties in the ribose units and on the 2 N–H atoms. The most negative
The computed binding energies (in kcal mol− 1) of nucleoside-water and regions were observed on the carbonyl oxygen extension and the N7
deoxynucleoside-water complexes using BP86, B3LYP-D3, M06-2X, M06L, M06- atom. The higher negative value at the N7 on guanosine compared to the
2X-D3 functional for the most stable geometries. adenosine is attributed to the presence of a nearby carbonyl group [17].
Complex BP86 B3LYP-D3 M06-2X M06L M06-2X-D3 In the pyrimidine nucleosides, the most positive regions were
A-H2O − 15.17 − 14.19 − 11.97 − 13.26 − 13.54 observed on the –OH hydrogen atoms in the ribose moiety and close to
G-H2O − 14.55 − 12.29 − 11.56 − 11.35 − 13.98 the amine groups attached to the C4 carbon (cytidine) or 3 N–H atoms
C-H2O − 15.66 − 14.30 − 11.54 − 12.04 − 12.24 (thymidine and uridine). The most negative regions in all the pyrimidine
T-H2O − 13.21 − 14.13 − 10.90 − 11.09 − 10.42 bases were on the extension of the carbonyl oxygen atom of the nucle­
U-H2O 13.80 14.02 10.55 10.89 10.49
obases. The cytidine molecule has the highest negative region at the C2
− − − − −
dA-H2O − 14.67 − 13.80 − 16.85 − 12.26 − 17.22
dG-H2O − 14.68 − 14.85 − 15.45 − 14.22 − 16.77 carbonyl oxygen atom with a value of − 50.4 kcal mol− 1, while the –OH
dC-H2O − 15.38 − 16.21 − 18.02 − 15.06 − 18.41 oxygen atoms on the sugar unit have considerably low negative poten­
dT-H2O − 11.57 − 13.64 − 15.85 − 12.64 − 16.61 tials. In thymidine and uridine, the highest negative values are found on
dU-H2O 11.61 13.45 15.89 12.84 16.41
− − − − −
the C4 carbonyl oxygen atoms.
During the complex formation process, the observed positive region
protonated uridine and thymidine were − 6.2 and − 5.1 kcal/mol in a molecule can interact with any negative location of the other
respectively. molecule, thereby giving rise to a directional interaction [61]. Thus, one
The computed enthalpy changes for all the hydrated complexes are can anticipate the increase or decrease in the positive or negative values
all negative indicating the process to be exothermic. Furthermore, the for the observed complex. Upon hydration of adenosine and guanosine,
Gibbs free energy change was also negative demonstrating the hydration we observe most of the positive/negative regions turn to a yellow shade.
process is spontaneous and thermodynamically favorable. The negative In the A-H2O complex, the Vs,max on the hydrogen atom of water
ΔG◦ and ΔH◦ values imply that the formation of the water complex is a molecule got reduced to 31.8 from 45.2 kcal mol− 1, while the Vs,min on
spontaneous and enthalpy driven process. The computed entropies were oxygen atom got increased to − 20.8 from − 38.3 kcal mol− 1 when
also negative implying that the system moves to a more constrained compared to the isolated water molecule. While in the nucleoside there
from the free fluctuating molecules along with the structural modifica­ has been a decrease in the Vs,max values of the –OH hydrogen atoms.
tion which is evident from the computed deformation energy. The en­ Since the Vs,min on adenosine and guanosine is observed on the 7 N, and
tropies were in the range of − 37.05–− 31.56 cal/mol K. Our computed Vs,max on the 5′ –OH hydrogen atom, the water complex prefers to
hydration entropy and enthalpy do not show any appreciable change for attach through them. In the pyrimidine-based nucleosides, the second-
all the nucleoside-water complexes, conforming to the experimental highest Vs,max were found on the 7 N–H group or on the 3 N–H
findings. extension. These Vs,max was closer to the Vs,min on oxygen atom on 2C
= O and matches with the hydrogen bonding distance and hence the
water molecule binds to this location. Although the highest Vs,max were
3.3. Nature of intermolecular interaction observed on the 5′ C-OH, the cooperativity between the 7 N–H and O– –C
helps in deciding the water location.
Molecular electrostatic attraction between individual molecules in In the deoxynucleoside, the absence of the 2′ –OH unit increased the
complexes are considered to be one of the important driving forces for Vs,max of 3′ –OH hydrogen atom. It should be pointed out that in the
their formation [58]. To investigate the above hypothesis, the electro­ nucleosides, the 2′ and 3′ –OH groups exist in hydrogen bonding
static potential for the nucleosides and deoxynucleosides were resulting in the lowering of Vs,max on these hydrogen atoms. The
computed at the M06-2X-D3/6–311 + G(d,p) level of theory. The results observed Vs,max on the 5′ and 3′ –OH groups were of similar magnitude.
are visualized in Fig. 2, as electrostatic potential mapped onto the Thus, in the deoxynucleosides, the water binds with the 3′ –OH hydrogen
isoelectronic surface for the free nucleoside, deoxynucleoside, and their of the ribose unit and with the nearest most negative part of the purine/
water complexes at the 0.001 electrons/Bohr3 isodensity surface pyrimidine base, except the dG-H2O system. It is worth mentioning that
[59,60]. The electron-rich regions are shown in red color and the the most negative regions were observed on the carbonyl oxygen
electron-deficient region is depicted by the blue color. Furthermore, the extension and the N7 atom.
location of selective positive and negative potentials values designated The theoretical basis of QTAIM, EDA and NCI-RDG analysis are
as Vs,max, and Vs,min respectively along with their quantitative values are provided in the supporting information along with in detailed analysis
shown in black and blue color. In the water molecule the Vs,max is on the various interaction observed in the nucleoside-water and
observed on the hydrogen atoms with values of 45.2 kcal mol− 1, while deoxynucleoside-water complexes. In the nucleoside-water complexes,
the Vs,min is observed on the oxygen atom with a value of − 38.3 kcal we observe two intermolecular BCPs, while in deoxynucleoside-water
mol− 1. In the adenosine molecule, the most positive region is observed complexes we observe four BCPs except for the dG-H2O complex. The
near the 5′ –OH hydrogen atom, and the other two –OH groups in the ρ(r) and ∇2 ρ (r) values are all positive, which implies that the hydrogen
ribose units at C2′ and C3′ has the positive values of 54.9 and 29.3 kcal bonds observed cannot be classified as very strong ones. A comparison of
mol− 1 respectively. The most negative regions were observed closer to AIM topological parameters between G-H2O and dG-H2O which have
the nucleobase nitrogen atoms N3, N1, and N7 with values of − 41.5, very similar water binding site show that the electron density of dG-H2O
− 38.9, and − 33.1 kcal mol− 1. Similar to adenosine, the other purine is on the higher side, implying their bonds to be stronger than in G-H2O.
nucleoside, guanosine has the most positive regions closer to the –OH

Table 3
Computed theormodyanmical parameters for the hydrated complexes with nucleoside and deoxynucleoside molecules computed at 298 K using M06-2X-D3/6–311 +
G(d,p) level of theory.
Nucleobase-H2O -ΔGo (kcal/mol) -ΔHo (kcal/mol) -ΔSo (cal/mol K) Deoxynucleobase-H2O -ΔGo (kcal/mol) -ΔHo (kcal/mol) -ΔSo (cal/mol K)

A-H2O 5.83 16.83 36.87 dA-H2O 2.18 12.02 33.01

G-H2O 2.23 13.27 37.05 dG-H2O 2.48 13.30 36.30
C-H2O 1.72 11.36 32.33 dC-H2O 3.69 14.39 35.89
T-H2O 0.18 9.63 31.68 dT-H2O 2.19 12.20 33.59
U-H2O 0.36 9.77 31.56 dU-H2O 1.97 12.03 33.78

5
V. Natarajan Sathiyamoorthy et al. Computational and Theoretical Chemistry 1204 (2021) 113422

Fig. 2. Molecular electrostatic surface potentials mapped on corresponding 0.001 a.u electron density isosurface for nucleoside and deoxynucleoside and their water
complexes along with the calculated Vs,max and Vs,min values. Color ranges, in kcal/mol: red, > 25; yellow between 25 and 10; green, between 10 and − 10; blue,
> − 10.

6
V. Natarajan Sathiyamoorthy et al.
EDA analysis shows that among the attractive terms ΔEelst term accounts
for nearly 60 % contribution. The orbital interaction in all the complexes
is nearly identical with nearly 30 % contribution to the total interaction
energy. Comparison between the nucleoside-water and
deoxynucleoside-water complexes, the dispersion term is more pre­
dominant in the deoxynucleoside-water complex. In the NCI plot we
observe spikes arising due to the intermolecular interaction of the 5′ –OH
hydrogen-water, and N3atom in adenosine and hydrogen atom of water.
While such spike is not observed for the deoxyadenosine, due to the lack
of such interaction. In the case of deoxycytidine, we observe two weak
intramolecular hydrogen bonding between the 1′ C–H, 2′ C–H, and
carbonyl oxygen. This intramolecular hydrogen bonding is not observed
in the case of purine-based deoxynucleosides. In the dC-H2O complex,
we observe two new spikes other than observed in deoxycytidine, at
− 0.029 and − 0.024 a.u. which are due to the strong hydrogen bonding
by C–– O⋅⋅⋅HOW and 3′ –OH⋅⋅⋅Ow.
3.4. Comparison of nucleoside-water, deoxynucleoside-water interactions
with nucleobase-water complex.
It is worth comparing the nature of interactions in nucleobase-water
and nucleoside/deoxynucleoside-water complexes, as it would help in
understanding the water interaction in free nucleobases and DNA/RNA
molecules. In the free nucleobases, the water is bound to carbonyl ox­
ygen and the amine hydrogen except for the adenine molecule, wherein
water bonding occurs through the N3 nitrogen and amine hydrogen. In
the case of nucleosides and deoxynucleosides, the water binds though
it’s one of the hydroxyl groups in the ribose ring. The charge delocal­
ization in the nucleobase-water mainly occurs close to the vicinity of the
water molecule, whereas in the nucleosides and deoxynucleosides the
charge transfer occurs through the molecules. The binding energies in
the nucleobase-water were in the range of − 12.56–13.64 kcal mol− 1,
which is closer to the binding energy observed in the case of nucleoside-
water complexes. Furthermore, binding energies do not show any sub­
stantial change for nucleobase/nucleoside/deoxynucleoside, which
conforms to the experimental findings on their hydration. In the AIM
analysis, the existence of a strong hydrogen bond with noncovalent
nature and electrostatic dominance was observed in nucleobase-water
complexes. In the nucleoside/deoxynucleoside-water complexes, we
observe several medium to strong hydrogen bonds with noncovalent
nature. EDA analysis shows the electrostatic interaction to be more
dominant in all complexes. NCI-RDG analysis shows hydrogen bonding
interaction in the nucleobase-water and nucleoside-water complexes.
The existence of weak van der Waals interactions in the
deoxynucleoside-water complexes making them more stable than the
other two systems.
4. Conclusion
In summary, the present study sheds light on the nature of in­
teractions between nucleoside and deoxynucleoside with water mole­
cules. In the most stable purine-based adenosine-water (A-H2O) and
guanosine-water (G-H2O) complexes, the water molecule binds through
the N7 nitrogen atom of the five-member ring and the 5′ –OH group in
the ribose unit. In the pyrimidine-based nucleosides, thymidine-H2O (T-
H2O), and uridine-H2O (U-H2O), the water molecule is linked by the
carbonyl oxygen atom and the N3-H hydrogen atom. In the cytidine-
H2O, the water molecule is bonded with cytidine through the N3 ni­
trogen and the N7-H linked to the C4 carbon. In the deoxynucleosides,
the water binds through C3′ alcohol and N3 nitrogen or carbonyl oxygen
of deoxynucleosides. The interaction energy and binding energy of
nucleoside-water vary only a little. Comparison between nucleoside-
water and deoxynucleoside-water complexes show higher interaction
energies for deoxynucleoside-water complexes. Purine bases nucleoside-
water complexes are more stable than the pyrimidine bases nucleoside-
water complexes. While the reverse trend is observed in
7
Computational and Theoretical Chemistry 1204 (2021) 113422
deoxynucleoside-water complexes. The computer thermodynamics pa­
rameters ΔG◦ , ΔH◦ , and ΔS◦ values are negative. Our computed hy­
dration entropy and enthalpy do not show any appreciable change for all
the nucleoside-water complexes, which emulate the experimental
findings.
The main factors contributing to the stability of the water complex
were identified using MESP, AIM, NCI-RDG, and EDA analysis. MESP
shows that the most positive region is observed near the 5′ –OH
hydrogen atom of ribose unit in nucleosides, while the alcohol groups at
the 3′ C and 2′ C are in bonding and hence experience a considerably low
Vs,max. In the case of deoxynucleosides, the 3C’ alcoholic hydrogen has
Vs,max values closer to that of 5′ –OH hydrogen atom. Hence, in dG-H2O,
the water binds with the 5′ –OH hydrogen and the N7 atom of the purine
base. QTAIM analysis shows the presence of medium-strength hydrogen
bonds between water and nucleoside in their complexes. In the case of
deoxynucleoside-water complexes in addition to the 3-OH hydrogen
bonding with water, we notice the presence of 2′ C–H in ribose unit
bonding with oxygen in the water molecule. EDA analysis shows that
60% of attractive interactions are due to electrostatic attraction. The 2D
RDG plot shows new spikes after the hydration of nucleosides and
deoxynucleosides in the region − 0.02–− 0.03 a.u. which are due to the
intermolecular interaction of the 5′ –OH hydrogen-water, hydrogen
atom of water interacting with the nucleobase. In deoxynucleosides,
additional spikes due to the interaction of 2′ C hydrogen with water
oxygen were observed. We also observe the existence of several green
patches in the deoxynucleoside-water complexes, associated with the
weak van der Waal’s interactions which make them more stable than
nucleoside-water complexes.
CRediT authorship contribution statement
Venkataramanan Natarajan Sathiyamoorthy: Data curation,
Investigation, Methodology, Resources, Supervision, Writing – original
draft, Writing – review & editing. Ambigapathy Suvitha: Formal
analysis, Investigation, Visualization, Project administration. Ryoji
Sahara: Formal analysis, Investigation, Validation, Visualization.
Yoshiyuki Kawazoe: Resources, Software, Supervision.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgement
This work carried out did not receive any specific grant from funding
agencies in the public, commercial, and/or not-for-profit sectors. The
authors would like to thank the staff of the Center for Computational
Materials Science, Institute for Materials Research, Tohoku University,
and the supercomputer resources through the HPCI System Research
Project (Project ID: hphp200040).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.comptc.2021.113422.
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