Synthesis, crystal structure, Hirshfeld surface analysis, DNA binding, DNA cleavage activity and molecular docking of a new Schiff base nickel(II) complex

Article abstract of DOI:10.1080/07391102.2020.1784789

A mononuclear nickel(II) complex, [Ni(o-van-tris)₂]·2H₂O (o-van-tris = Schiff base derived from o-vanillin and tris(hydroxymethyl)aminomethane), has been synthesized and structurally characterized. The single crystal structure shows

Full text of DOI:10.1080/07391102.2020.1784789

Journal of Biomolecular Structure and Dynamics
ISSN: 0739-1102 (Print) 1538-0254 (Online) Journal homepage: https://www.tandfonline.com/loi/tbsd20
Synthesis, crystal structure, Hirshfeld surface
analysis, DNA binding, DNA cleavage activity and
molecular docking of a new Schiff base nickel(II)
complex
Jianfang Dong, Lei Gao, Bo Zhang, Tao Xu, Lei Wang, Jinming Kong & Lianzhi
Li
To cite this article: Jianfang Dong, Lei Gao, Bo Zhang, Tao Xu, Lei Wang, Jinming Kong & Lianzhi
Li (2020): Synthesis, crystal structure, Hirshfeld surface analysis, DNA binding, DNA cleavage
activity and molecular docking of a new Schiff base nickel(II) complex, Journal of Biomolecular
Structure and Dynamics, DOI: 10.1080/07391102.2020.1784789
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JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
https://doi.org/10.1080/07391102.2020.1784789
Synthesis, crystal structure, Hirshfeld surface analysis, DNA binding, DNA
cleavage activity and molecular docking of a new Schiff base nickel(II) complex
Jianfang Donga,b, Lei Gaoc#, Bo Zhanga, Tao Xua, Lei Wanga, Jinming Kongd
and Lianzhi Lia
b
aSchool of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, P. R. China; Department of Material Science, Shandong
c
Polytechnic Technician College, Liaocheng, Shandong, China; Zhong Yuan Academy of Biological Medicine, Liaocheng People’s Hospital
d
Affiliated to Shandong University, Liaocheng, China; School of Environmental and Biological Engineering, Nanjing University of Science and
Technology, Nanjing, China
Communicated by Ramaswamy H. Sarma
ABSTRACT
ARTICLE HISTORY
Received 7 February 2020
Accepted 15 June 2020
A mononuclear nickel(II) complex, [Ni(o-van-tris)2]ꢀ2H2O (o-van-tris ¼ Schiff base derived from o-vanillin
and tris(hydroxymethyl)aminomethane), has been synthesized and structurally characterized. The single
crystal structure shows a distorted octahedron geometry coordinated with Ni(II) atom, and 2 D plane
structure has formed by O–HꢀꢀꢀO hydrogen bond interactions. An analysis to ascertain intermolecular
interactions of the complex was performed based on the Hirshfeld surfaces and their associated two-
dimensional fingerprint plots. The binding properties of the nickel(II) complex with CT-DNA have been
investigated by spectroscopic methods and molecular docking. Absorption and fluorescence spectral
studies reveal that the complex interacts with DNA through hydrogen bond and hydrophobic interac-
tions with the DNA base pairs. Molecular docking studies show that the complex effectively docks in
the major groove of DNA. The DNA cleavage experiment was performed by gel electrophoretic assay,
indicating that DNA cleavage activity of the complex is concentration dependent and much sensitive
to ionic strength. The efficient cleavage mediated via hydrolytically cleaving pathway.
KEYWORDS
Schiff base nickel(II)
complex; Hirshfeld surface
analysis; DNA binding; DNA
cleavage; molecular docking
Abbreviations: DG: Gibbs free energy; CD: circular dichroism; CT-DNA: calf thymus deoxyribonucleic
acid; EB: Ethidium bromide; EDTA: ethylenediaminetetraacetic acid; FT-IR: Fourier transform infrared
spectroscopy; K: equilibrium binding constant; Ksq: linear Stern-Volmer constant; Tris: tris(hydroxyme-
thyl)aminomethane; UV: Ultraviolet
1. Introduction
these molecules can interact with DNA to affect its replica-
tion and transcription, causing DNA damage in cancer cells,
and resulting in cell death (Roos & Kaina, 2006; Hong et al.,
2014; Jiang et al., 2013). Transition metal complexes have
shown to play important roles in studying metal-based anti-
cancer drugs, probes for nucleic acid structure and artificial
Cancer, a widespread disease, is one of the second leading
causes of human death in the globe (Cattin et al., 2017). For
a long time, scientists have been making great efforts to
develop anti-cancer drugs. Numerous studies have suggested
that DNA is the primary target of anti-cancer drugs, because nuclease due to their efficiently binding and cleaving DNA.
CONTACT Lianzhi Li
lilianzhi1963@163.com
School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng, 252059, P. R. China
#Co-first author.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
J. DONG ET AL.
Scheme 1. Synthetic route for the preparation of the Ni(II) complex
Lots of nickel complexes have been synthesized and tested commercially used without further purification. All experi-
ments involving interaction with CT-DNA were performed in
10 mM Tris-HCl/10 mM buffer (pH 7.1). The DNA solution
for their DNA binding capacity and cleavage potential even
anticancer activities (Aramesh-Boroujeni et al., 2020;
Haribabu et al., 2015; Kondori et al., 2020; Li et al., 2016; Niu
et al., 2015; Shiri et al., 2020; Wang et al., 2019).
gave a ratio of UV absorbance at 260 and 280 nm (A260/A280
)
of 1.8-1.9, indicating that the DNA was sufficiently free of
protein (Marmur, 1961). The DNA concentration per nucleo-
tide was determined by absorption spectroscopy using the
Transition metal nickel is an essential trace element for
life, it involved in some important enzymes such as urease,
carbon monoxide dehydrogenase and hydrogenase (Raman
& Sobha, 2012; Oliveri & Vecchio, 2016). On the other hand,
nickel complexes have been widely studied for their toxicity,
carcinogenic nature and chemotherapeutic application in the
aspects of medicine (Kong et al., 2008), and interactions of
nickel complexes with DNA were also investigated (Zhao
et al., 2016; Wei et al., 2016). Schiff bases play an important
role as chelating ligands in coordination chemistry due to
their chemical stability and structural versatilities.
Tris(hydroxymethyl)aminomethane (Tris) is a non-toxic ami-
noalcohol, which has been widely used in biochemistry and
molecular biology (Pannuru et al., 2018). Metal complexes of
Tris-containing Schiff base are known to have a broad spec-
trum of biological activities including anti-tumour, antibiotic,
anticancer, antihistamine, antifungal, anti-inflammatory and
antidiabetic etc.(Lee et al., 2015; Halevas et al., 2017; Dey
et al., 2002; Rehder et al., 2002). In addition, catalytic epoxi-
dation properties and magnetic properties of Tris-containing
Schiff base metal complexes have been reported (Sui et al.,
2007; Hu et al., 2008). However, there are little reports on
the DNA interactions of Tris-containing Schiff base metal
complexes. Therefore, herein we have synthesized a Tris
Schiff base nickel(II) complex, determined its crystal structure,
performed its Hirshfeld surface analysis and studied its inter-
action with DNA using spectroscopies and molecular docking
method. In addition, the pBR322 DNA cleavage activity of
the complex has been investigated by gel electrophoresis.
These results would be expected to help understand the
binding mode of this kind of complex to DNA, and useful to
explore new anticancer agents, modify or detect
bio-molecules.
molar absorption coefficient (6600 Mꢁ1cmꢁ1
(Reichmann et al., 1954).
) at 260 nm
Elemental analysis for C, H and N was performed on a
Perkin-Elmer 2400 II analyzer. IR spectrum was obtained on a
Nicolet 5700 FT-IR spectrometer in the range of
4000–400 cmꢁ1. Fluorescence spectra were recorded on an
LS55 spectrofluorometer equipped with 1.0 cm quartz cells.
UV–visible absorption spectra were measured on UV–2550
spectrophotometer with a 1.0 cm cell. Circular dichroism (CD)
spectra measurements were recorded on a Jasco J–810 spec-
tropolarimeter using a 1.0 mm path length quartz cuvette.
2.2. Synthesis of the complex
Tris(hydroxymethyl)aminomethane (0.121 g, 1 mmol) was dis-
solved in methanol (10 mL) and added successively to a
methanol solution (3 mL) of o-vanillin (0.152 g, 1 mmol). The
mixture was then stirred at 323 K for 2 h. Subsequently, an
aqueous solution (2 mL) of nickel chloride hexahydrate
(0.119 g, 0.5 mmol) was added dropwise and stirred for
another 5 h. The resultant solution was filtered and kept at
room temperature for 10 days, whereupon green block-
shaped crystals suitable for X-ray diffraction were obtained.
Yield: 85%. m.p. 223–225 ꢂC. Anal. Calcd. for C24H36N2NiO12:
C 47.78%, H 6.01%, N 4.64%. Found: C 47.74%, H 6.10%, N
4.48%. IR (KBr pellets,/cmꢁ1, s, strong absorption; m, middle
absorption; w, weak absorption): 3,210 (s), 2,913 (m), 2,861
(m), 1,628 (s), 1,600 (m), 1,541 (m), 1,466 (m), 1,439 (m),
1,366 (m), 1,309 (m), 1,243 (w), 1,212 (m), 1,167 (w), 1,080
(w), 1,051 (w), 1,018 (w), 990 (m), 976 (m), 855 (m), 751 (w),
736 (m), 640 (w), 565 (w), 528 (w), 499 (w), 469 (w). The syn-
thetic route for the preparation of the Ni(II) complex was
shown in Scheme 1.
2. Experimental
2.1. Chemicals and instruments
2.3. X-ray crystallography
All the chemicals and biological agents including o-Vanillin,
tris(hydroxymethyl)aminomethane (Tris), nickel chloride hexa-
hydrate and CT-DNA, pBR322 DNA etc were AR grade or bio-
A single crystal of the complex with dimensions of 0.50 mm
ꢃ 0.43 mm ꢃ 0.40 mm was mounted in a glass capillary and
data were collected on a Bruker Smart-1000 CCD diffractom-
chemical purity. They were all obtained from the best eter. Intensity data were collected with graphite

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
3
Table 1. Crystallographic and Structure Refinement Data for the complex.
adding different amounts of the nickel(II) complex solutions
to a fixed concentration of DNA solutions. The complex-DNA
solutions were incubated for 1 h before the absorption spec-
tra were recorded. Due correction was made for the absorb-
ance of the nickel(II) complex itself.
For fluorescence quenching experiments, a solution of the
nickel(II) complex was added to CT-DNA solution treated
with EB for 30 min in the buffer solution. All samples were
excited at 510 nm and emission spectra were recorded at
540-700 nm. Each spectrum was recorded at a scan speed of
200 nm/min and slit width of 7 nm.
CD spectra were carried out on J-810 spectropolarimeter
at room temperature with a quartz cell of 1 cm path length
by varying the complex/CT-DNA ratio in the buffer. Each
sample solution was scanned in the range of 220-320 nm
with a scan speed of 100 nm/min and 1 s response time.
Each spectrum was gained after three accumulations from
which the buffer background had been subtracted.
Empirical formula
C24H36N2NiO12
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system, space group
Unit cell dimensions
a (Å)
603.26
298(2)
0.71073
Monoclinic, P2(1)/c
11.9520(10)
11.0359(11)
b (Å)
c (Å)
20.664(2)
a ¼ c (ꢂ)
90
b (ꢂ)
97.6000(10)
2701.7(5)
4, 1.483
0.784
Volume (Å3)
Z, Calculated density (Mg/m3)
Absorption coefficient (mmꢁ1
F(000)
)
1272
Crystal size (mm)
0.50 ꢃ 0. 43 ꢃ 0.40
2.52 ꢁ 25.02
99.6
ꢁ14,14; ꢁ13,12; ꢁ14,24
13635 / 4746
0.0324
h Range for data collection (ꢂ)
Completeness to theta ¼ 25.02 (%)
Limiting indices
Reflections collected / unique
R(int)
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [ I > 2r(I)]
R indices (all data)
4746 / 5 / 358
1.014
R1 ¼ 0.0348, wR2 ¼ 0.0802
R1 ¼ 0.0515, wR2 ¼ 0.0919
0.430 and ꢁ0.359
Largest difference in peak and hole (e/Åꢁ3
)
2.6. DNA cleavage experiment
For the gel electrophoresis analysis, the supercoiled (SC) pBR
322 DNA was treated with the nickel(II) complex in reaction
mixture solution. The solution was incubated for 3 h at 37 ꢂC,
then a quench buffer solution containing bromophenol blue
(0.25%) and sucrose (40%) was added. In the ensuing step,
samples were immediately loaded on 0.8% agarose gel for
electrophoresis in TBE buffer (89 mM Tris base, 89 mM bor-
acic acid, 2 mM EDTA) containing 0.5lg/ml EB at 40 V for 2 h.
Finally, the gel was photographed under UV light.
monochromated Mo Ka radiation (k＝0.071073 nm) at 298(2)
K with the x-2h scan technique. The structure was solved by
direct methods using SHELXLS-2014 and refined against F2
by full matrix least squares using SHELXL-2014 (G. M.
Sheldrick, 1997). The organic hydrogen atoms were gener-
ated geometrically and allowed to refine using a riding
model. The water hydrogen atoms were located from differ-
ence Fourier maps and refined with distance restraints
d(O–H) ¼ 0.85 Å. Multi-scan empirical absorption corrections
were applied to the data using the program SADABS (G. M.
Sheldrick, 1999-2003). A summary of pertinent crystal data,
experimental details and refinement results are shown in
Table 1. Crystallographic data for complex have been depos-
ited with the Cambridge Crystallographic Data Center, CCDC
No. 832378. Copies may be obtained free of charge from
www.ccdc.cam.ac.uk/conts/retrieving.html or from the CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK (email: depos-
it@ccdc.cam.ac.uk) .
2.7. Molecular docking
The AutoDock 4.2 software with an accessory program
AutoDock Tools (ADT) (Morris et al., 2009) was used to carry
out the docking studies of the nickel(II) complex binding to
DNA. The crystal structure of DNA(PDB ID: 355 D) of B-DNA
dodecamer d(CGCGAATTCGCG)2 were downloaded from the
RSCB Protein Data Bank (http://www.rscb.org), and the CIF
file of the nickel(II) complex was converted to the PDB for-
mat using Mercury software (http://www.ccdc.cam.ac.uk/).
For docking the DNA PDB file was first read in ADT, all the
water molecules were removed and polar hydrogens were
added. Gasteiger charges were added and non-polar hydro-
gens were merged for each atom. Then DNA file was saved
with pdbqt extension. Secondly, ADT read the nickel(II) com-
plex as the ligand, determined the best root and rotatable
bonds then saved the ligand as another pdbqt extension file.
The grid box was set (52 ꢃ 52 ꢃ 94 Å) with a grid spacing of
0.375 Å to be used for the molecular docking. When
AutoDock was running, parameters used as follows: number
of run, 30; population size, 150; maximum number of energy
evaluations, 2500 00; numbers of generations, 27000. A max-
imum of 10 conformers was considered for the ligand, and
the root-mean-square deviation (RMSD) cluster tolerance was
2.4. Hirshfeld surface
Hirshfeld surface calculation was performed using the
CrystalExplorer package ver. 3.1 (Wolff et al., 2012). Crystal struc-
ture was imported from CIF file. Hirshfeld surface was generated
for complex molecule using high resolution and mapped with
the dnorm functions. 2 D fingerprint plots were prepared with the
use of the same software. The dnorm surfaces are mapped over a
fixed color scale of ꢁ0.701 (red) to 1.798 a.u. (blue). The 2 D fin-
gerprint plots are displayed by using the translated 0.6–2.6 Å
range, and including reciprocal contacts.
2.5. DNA binding experiments
All the DNA binding experiments were carried out in 10 mM set to 2.0 Å in running autodock. Ten best conformations
Tris-HCl/10 mM NaCl, pH 7.1 buffer solutions. For UV–Vis based on docking energy were considered for the nickel(II)
absorption experiments, a set of solutions were prepared by complex, and the conformer with the lowest energy was

4
J. DONG ET AL.
Table 2. Selected bond lengths (Å) and bond angles (ꢂ) of the complex.
Ni1-N1
Ni1-O1
Ni1-O7
2.0150(19)
2.1454(18)
2.0182(17)
92.50(7)
91.73(7)
97.93(8)
78.75(7)
85.18(7)
90.60(7)
169.09(7)
93.54(7)
Ni1-N2
Ni1-O4
Ni1-O9
N1-Ni1-O9
N1-Ni1-N2
O9-Ni1-N2
O7-Ni1-O1
N2-Ni1-O1
O7-Ni1-O4
N2-Ni1-O4
2.035(2)
2.2015(18)
2.0208(17)
99.74(7)
164.78(8)
91.02(8)
170.05(7)
91.58(7)
91.26(7)
78.18(7)
N1-Ni1-O7
O7-Ni1-O9
O7-Ni1-N2
N1-Ni1-O1
O9-Ni1-O1
N1-Ni1-O4
O9-Ni1-O4
O1-Ni1-O4
Table 3. Hydrogen bond lengths (Å) and bond angles (ꢂ) of the complex.
Lable
D ꢁ HꢀꢀꢀA
d(D ꢁ H) d(H ꢁ A) d(D ꢁ A) /(DHA)
(Figure 3)
O1 ꢁ H1dꢀꢀꢀO11
O11 ꢁ H11cꢀꢀꢀO5
O11 ꢁ H11dꢀꢀꢀO12
0.85
0.85
0.85
0.82
0.82
0.85
0.82
0.85
0.82
0.85
1.84
2.13
1.98
1.92
1.90
1.90
1.90
1.79
1.89
2.02
2.686(3) 175.9
2.977(3) 170.8
2.823(3) 171.2
2.686(3) 155.7
2.670(2) 157.0
2.749(3) 177.7
2.681(3) 159.2
2.635(3) 173.9
2.680(3) 160.7
2.867(3) 174.3
9
8
#1
O3 ꢁ H3ꢀꢀꢀO2
2
4
1
5
7
6
3
#2
Figure 1. ORTEP view of the molecular structure and atom-labeling scheme of
the nickel(II) complex. Thermal ellipsoids are drawn at 30% probability level.
O2 ꢁ H2ꢀꢀꢀO9
O4 ꢁ H4fꢀꢀꢀO3#2
O5 ꢁ H5aꢀꢀꢀO8#3
O12 ꢁ H12fꢀꢀꢀO6#3
O6 ꢁ H6ꢀꢀꢀO5#4
selected as binding mode to use for further analysis.
Visualization of the docked pose has been done by using
UCSF Chimera (Pettersen et al., 2004).
O12 ꢁ H12gꢀꢀꢀO10#5
Symmetry codes for complex: #1 ¼ 1 ꢁ x, y ꢁ 0.5, 0.5 ꢁ z #2 ¼ 1 ꢁ x, y þ 0.5,
0.5 ꢁ z #3 ¼ ꢁx, y þ 0.5, 0.5 ꢁ z #4 ¼ ꢁx, y ꢁ 0.5, 0.5 ꢁ z #5 ¼ x, y þ 1, z.
3. Results and discussion
ligands coordinate to Ni(II) ion forming a six-coordinated
structure. Four O atoms and two N atoms around Ni atom
present a distorted octahedron. The O1, O4, O7 and O9
atoms locate in the equatorial plane, and N1, N2 occupy the
axial position of the octahedron. The bond angle of
N1–Ni1–N2 ¼ 164.83(8)ꢂ is serious deviated from the ideal
value of 180ꢂ and Ni1 atom lies 0.0148(9) Å above the equa-
torial plane. The bond lengths from Ni atom center to donor
atoms are Ni1-N1 ¼ 2.0150(19), Ni1-N2 ¼ 2.035(2), Ni1-
O1 ¼ 2.1454(18), Ni1-O7 ¼ 2.0182(17), Ni1-O9 ¼ 2.0208(17)
and Ni1-O4 ¼ 2.2015(18) respectively, as listed in Table 2. The
complex has both intra- and intermolecular hydrogen bond-
ing in the crystal structure. Hydrogen bond parameters are
given in Table 3. Two lattice water molecules are linked
together by an O11 ꢁ H11dꢀꢀꢀO12 hydrogen bond, and they
are connected to the main molecule by O11 ꢁ H11cꢀꢀꢀO5 and
O12 ꢁ H12fꢀꢀꢀO6 (-x, y þ 0.5, 0.5-z) hydrogen bonds. Together
with the other intermolecular hydrogen bonds resulted into
2 D plane structure (Figure 2).
3.1. Characterization of the ligand and complex
In IR spectra, the very broad absorption at 3,340 cmꢁ1 for lig-
and and 3,210 cmꢁ1 for nickel complex are assigned to the
O-H stretching vibration. Generally, the O-H stretching vibra-
tion for water appears above 3,400 cmꢁ1. The shift of this
band towards lower wave number and its broadness indicate
the presence of strong hydrogen bonding which is also con-
firmed from its crystal structure (Thakurta et al., 2009). Two
weak peaks observed at 2,947 and 2,830 cmꢁ1 for ligand and
at 2,913 and 2,861 cmꢁ1 the complex are likely to be due to
the aromatic and aliphatic C–H stretches (Nakamoto, 1997).
In the IR spectrum of ligand, the very sharp absorption at
1,640 cmꢁ1 and strong absorption at 1,230 cmꢁ1 can be
assigned to the imine group (C ¼ N) and (C–O) stretching fre-
quency. For nickel complex, the corresponding bands of
m(C ¼ N) and m(C–O) appear separately at 1,628 and
1,212 cmꢁ1, suggesting N and O atoms are involved in
coordination. In the nickel complex, new absorption weak
bands at 499 and 469 cmꢁ1 can be reasonably assigned the
3.3. Hirshfeld surface analysis of the nickel(II) complex
ꢀ
Ni–O and Ni–N bonds, respectively (Vanco et al., 2008).
The formation of ligand was also confirmed by NMR spec-
tra. H NMR (400 MHz, DMSO-d6) d: 14.65 (s, 1H, ArOH), 8.47
(s, 1H, N ¼ CH), 6.95 (dd, 1H, J ¼ 0.8, 6.4 Hz, Ar-H), 6.89 (dd,
1H, J ¼ 0.8, 6.4 Hz, Ar-H), 6.58 (t, 1H, J ¼ 6.4 Hz, Ar-H), 4.79 (s,
3H, OH), 3.74 (s, 3H, CH3), 3.61 (s, 6H, CH2).
To study the nature of intermolecular contacts, Hirshfeld sur-
faces (HS) analysis (Figure 3) were presented with dnorm (nor-
malized contact distance) function based on both de and di,
and the van der Waals radii (ri) of the atom, given by the
equation (Mckinnon et al., 2007):
1
ð
Þ
ð
Þ
dnorm
¼
di ꢁ ri =ri þ de ꢁ ri =ri
(1)
3.2. Description of the structure of the
nickel(II) complex
de is distance from a point on the surface to the nearest
nucleus outside the surface and di is distance from a point
on the surface to the nearest nucleus inside the surface. For
The structure of [Ni(o-van-tris)2]ꢀ2H2O, determined by X-ray
crystallography, involve the double Schiff base ligand (o-van- the dnorm map of Hirshfeld surfaces, the red regions indicate
tris). As shown in Figure 1, the double tridentate Schiff base the interatomic contacts shorter than the sum of van der

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
5
Waals radii, while the blue and white regions are recognized area labeled 8 and 9 are associated with O11 ꢁ H11cꢀꢀꢀO5
interatomic contacts greater and equal to the sum of van and O1 ꢁ H1cꢀꢀꢀO11 hydrogen bonds occurring between the
der Waals radii, respectively. The dnorm map of the nickel(II) main molecule and another lattice water molecule with
complex indicates nine deep-red regions on the surface hydrogen bonds distance 2.13 Å and 1.84 Å, respectively. The
labeled 1-9, attributed to O ꢁ HꢀꢀꢀO strong hydrogen bonds. adjacent a pair of red spots dots labeled 5 and 6 represent
The red area labeled 7 correspond to hydrogen bond O5 ꢁ H5aꢀꢀꢀO8
and
O6 ꢁ H6ꢀꢀꢀO5
hydrogen
bonds.
(O12 ꢁ H12fꢀꢀꢀO6) formed by one lattice water molecule with Additionally, three deep red regions labeled 1, 2 and 4 are
short distance 1.79 Å. The area labeled 3 is corresponding to corresponding to and
O4 ꢁ H4fꢀꢀꢀO3,
O3 ꢁ H3ꢀꢀꢀO2
the other hydrogen bond (O12 ꢁ H12gꢀꢀꢀO10) of the lattice O2 ꢁ H2ꢀꢀꢀO9 hydrogen bonds interaction with adjacent com-
water molecule with bond distance 2.02 Å. While the red plex molecules forming a dimer. The last three red regions
Figure 2. Two dimensional plane structure formed by intermolecular hydrogen bonds viewing along the c axis with hydrogen bonds labeled.
Figure 3. Hirshfeld surface of the nickel(II) complex mapped with dnorm function, hydrogen bonds were labeled and marked with green dashed lines.

6
J. DONG ET AL.
Figure 4. The full two-dimensional fingerprint plot (middle) and those delineated into HꢀꢀꢀH (a), OꢀꢀꢀH/HꢀꢀꢀO (b), CꢀꢀꢀH/HꢀꢀꢀC (c), OꢀꢀꢀO (d), OꢀꢀꢀC/CꢀꢀꢀO (e) and NꢀꢀꢀH/
HꢀꢀꢀN (f) contacts of the nickel(II) complex, showing their percentage contributions to the Hirshfeld surface.
along with small red spots are related to O ꢁ HꢀꢀꢀO and respectively, to the total Hirshfeld surfaces of the
C ꢁ HꢀꢀꢀO (not labeled) hydrogen bonds play important role nickel(II) complex.
in forming a supramolecular structure.
The two-dimensional fingerprint plot can explore and
quantify the contribution of the intermolecular contacts in
3.4. DNA binding studies
the crystal (Rohl et al., 2008). As shown in Figure 4, the
major contribution to the overall Hirshfeld surfaces of the
nickel(II) complex comprised HꢀꢀꢀH, OꢀꢀꢀH/HꢀꢀꢀO and CꢀꢀꢀH/
HꢀꢀꢀC contacts (the total percentage is 99.3%). The others
only remained 0.7% including OꢀꢀꢀO, OꢀꢀꢀC/CꢀꢀꢀO and NꢀꢀꢀH/
HꢀꢀꢀN trivial contacts. In Figure 4a, the intermolecular HꢀꢀꢀH
interactions are predominant contributing 56.4% to the total
HS. The 2 D fingerprint plot of the (di, de) points is character-
ized by an end point which points to the origin with di ¼ de
ꢄ 1.0 Å. As shown in Figure 4b, the OꢀꢀꢀH/HꢀꢀꢀO contacts
(accounted for 24%) are depicted as a pair of sharp spikes in
the 2 D fingerprint plots with de þ di ꢄ 2.0 Å. As shown in
the Figure 4c, the CꢀꢀꢀH/HꢀꢀꢀC contacts occupy the symmet-
rical wings of the 2 D fingerprint plots with di þ de ꢄ 2.62 Å,
covering 18.9% of the total Hirshfeld surface. While the CꢀꢀꢀH
intermolecular interactions (Figure 5) show a larger contribu-
tion (10.7%) than the HꢀꢀꢀC counterpart (8.1%). Additionally,
the OꢀꢀꢀO, OꢀꢀꢀC/CꢀꢀꢀO and NꢀꢀꢀH/HꢀꢀꢀN inter-atomic contacts
3.4.1. UV spectroscopic study
Hyperchromism and hypochromism are the spectral features
of DNA concerning of its double helix structure, hyperchrom-
ism means the breakage of the secondary structure of DNA,
and hypochromism means the DNA binding mode of com-
plex is electrostatic effect or intercalation which can stabilize
the DNA duplex (Zhang et al., 2006). As shown in Figure 6a,
when the nickel(II) complex was added to CT-DNA, it took
on gradual decreasing of CT-DNA absorption at 260 nm upon
addition of complex, indicating interaction of the complex
with DNA. The hypochromism generated by the nickel(II)
complex could make a contraction in the helix axis of CT-
DNA by electrostatic binding to the phosphate group of
DNA backbone or by partial intercalation act as a ‘‘wedge’’
to pry apart one side of a base pair stack (Zhou, & Yang,
200Zhou and Yang, 62006). The interaction might results in a
static bend or kink in the helix, which lead to a reduction in
helix end-to-end distance and cause the hypochromism of
are clearly visible as scattered points in the fingerprint plots DNA (Zhou, & Yang, 200Zhou and Yang, 62006). The reduced
(Figure 4d–f) with de þ di ꢄ 3.2 Å, de þ di ꢄ 3.7 Å, de þ di ꢄ absorption of DNA in the presence of nickel(II) complex is
3.1 Å, respectively. They contribute 0.3%, 0.3% and 0.1%, due to the formation of ground state complex from

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
7
Figure 5. The two-dimensional fingerprint plot of CꢀꢀꢀH (left) and HꢀꢀꢀC (right) contacts of the nickel(II) complex, showing their percentage contributions to the
Hirshfeld surface.
intermolecular interactions, which can be represented as competitive binding experiment using EB as a probe was car-
below:
ried out. As shown in Figure 7, the increasing of the concen-
trations of the nickel(II) complex resulted in a gradual
decrease in the fluorescence intensity at 592 nm for the
DNA-EB system, indicating that the complex could displace
EB bound to DNA or destabilize the excited state of DNA-
bound EB (Baguley & Le Bret, 1984). This behavior suggested
that groove binding interaction would occur between the
nickel(II) complex and DNA (Kong et al., 2008), which can be
explained that the interaction can make a static bend or kink
in the helix and induce its conformational change, then
make partial EB to be taken off.
DNA þ complex $ DNA : complex
The equilibrium constant for this reaction can be repre-
sented as:
(2)
K ¼ ½DNA : complexꢅ=½DNAꢅ½complexꢅꢀ
(3)
where K is the equilibrium binding constant. According to
the Lambert–Beer’s law (Sarkar et al., 2013):
A0=ðA0ꢁAÞ ¼ eDNA=eb þ eDNA=ðebKccomplex
Þ
(4)
where A0 and A are the absorbance of DNA at 260 nm in the
absence and presence of the nickel(II) complex, and eDNA
and eb are the molar extinction coefficients of native DNA
and the bounded DNA, respectively. The double reciprocal
graph of 1/(A0ꢁA) versus 1/ccomplex yields a linear plot
(Figure 6b). The binding constant K can be estimated from
the ratio of the intercept to slope. From this plot
(R ¼ 0.9957), the calculated value of K is found to be
In order to measure the binding strength of the nickel(II)
complex with CT-DNA, the linear Stern–Volmer constant Ksq
was obtained from the linear Stern–Volmer equation
(Lakowicz, & Weber, 1973):
I0=I ¼ 1 þ Ksqr
(5)
where I0 and I are the fluorescence intensities in the absence
and presence of the nickel(II) complex, respectively, Ksq is a
linear Stern-Volmer constant and r is the concentration ratio
of the complex to DNA. The Stern–Volmer plot of DNA–EB
for the nickel(II) complex (Figure 7 inset) illustrates that the
quenching of EB bound to DNA by the complex is in good
agreement (R2 ¼ 0.9938) with the linear Stern–Volmer equa-
tion, which proves that the partial replacement of EB bound
to DNA by the nickel(II) complex results in a decrease in the
1.587 ꢃ 104
M
ꢁ1. Compared with the binding constant of
1.01 ꢃ 105 Mꢁ1 for [Ni(o-van-gln)(phen)(H2O)] previously
reported (Wei et al., 2016), the lower K value reveals that the
DNA binding ability is relative weak, which is due to the
hydroxyl-rich nickel(II) complex possessing many donor or
acceptor groups to form the strong hydrogen bonds with
nucleobases or phosphate groups present in the edge of
DNA. The result was also inferred from the following fluores-
cence, circular dichroism spectroscopy and molecular dock-
ing studies.
fluorescence intensity. The Ksq value of the complex (Ksq
¼
0.449) indicates that the interaction of this nickel(II) complex
with DNA is close to that of a reported copper(II) complex,
[Cu(naph-ser)(bipy)]ꢀ0.125CH2Cl2 (Ksq ¼ 0.53) (Li et al., 2011),
which suggests that the nickel(II) complex has a weaker
interaction with CT-DNA. This result reveals that the complex
3.4.2. The fluorescence spectroscopy study
The fluorescence measurement for the nickel(II) complex fails
to show emission whether with or without CT-DNA at ambi- is not able to involve intercalation with DNA to replace EB.
ent temperature in aqueous solution. To further investigate However, the complex at higher concentration would desta-
the interaction of the nickel(II) complex with DNA,
a
bilize the DNA-bound EB system more efficiently through

8
J. DONG ET AL.
Figure 6. Absorption spectra of calf thymus DNA (4.28 ꢃ 10ꢁ5 M) in the absence and presence of the nickel(II) complex at ccomplex ¼ 0, 0.252, 0.84, 1.68,
2.52 ꢃ 10ꢁ5 M, corresponding to the curves from a to e, respectively. The plot is 1/(A0ꢁA) vs. 1/ccomplex
.
Figure 7. Emission spectra of EB bound to CT-DNA in the absence (a) and pres-
Figure 8. CD spectra of CT DNA in absence and presence of the nickel(II) com-
plex, [DNA] ¼ 120 lM, r (the ratio of ccomplex/CDNA) ¼ 0, 0.2, 0.4, 0.6,
respectively.
ence of the nickel(II) complex (b–h), [EB] ¼ 25 mM, [DNA] ¼ 25 mM, r (the ratio
of ccomplex/cDNA) ¼ 0.2, 0.4, 0.6, 1.0, 1.6, 2.4, 4.8, respectively, kex ¼ 510 nm.
The arrow shows the increasing of the complex concentration. Inset: plot of I0/I
vs. r.
due to polynucleotide helicity (Rajendran, & Nair, 2006). The
Intercalation of small molecules to DNA can stabilize the
right-handed B conformation of CT DNA, and enhance the
intensities of both the bands. Simple groove binding and
electrostatic interaction of small molecules with DNA shows
little or no perturbations on the two bands (Maheswari, &
Palaniandavar, 2004). The CD spectra of CT-DNA after add-
ition of the nickel(II) complex are shown in Figure 8. On
increasing the concentration of the complex, neither the
positive band nor the negative band showed an obvious
change in ellipticity. So the intercalative binding mode might
be ruled out for the nickel(II) complex between DNA, and
groove binding or electrostatic interaction had happened
between them, the result was consistent with the UV absorp-
tion and fluorescence quenching measurements.
enhanced weak interaction (hydrogen bonds, hydrophobic
interaction or van der Waals interaction) with DNA surface
(Gopalakrishnan et al., 2017). The fluorescence quenching
result was consistent with UV absorption and following
molecular docking analysis results. Recently, Gao et al.
reported the synthesis, DNA/protein interaction and molecu-
lar docking of Ni(II) and Co(II) complexes constructed from
aroylhydrazone ligand, these complexes interacted with DNA
through an intercalation mode (Li et al., 2019a, 2019b; Li et
al., 2020). The different interaction modes between DNA and
metal complexes were determined by various ligands of
their complexes.
3.4.3. Circular dichroism study
Circular dichroism spectroscopy is a useful and sensitive
probe for the conformational changes of DNA in solution
and provides information about the binding of the complex
with DNA. The B-form conformation of CT-DNA shows two
conservative CD bands in the UV region; a positive band at
3.5. Molecular docking
Molecular docking is a useful technique to understand the
interaction between DNA and compound, which is very
important in drug discovery. In order to explore the potential
275 nm due to base stacking and a negative band at 245 nm binding mode and binding affinity, the nickel(II) complex

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
9
Figure 9. (a) Molecular docking of the nickel(II) complex at the major groove of DNA sequence d(CGCGAATTCGCG)2. (b) Hydrogen bonds formed by molecular
docking of the nickel(II) complex with DNA.
Figure 10. Gel electrophoresis diagram showing the cleavage of pBR322 DNA
incubated at 37 ꢂC for 3 h with different nickel(II) complex concentrations in
50 mM Tris–HCl/50 mM NaCl buffer. Lane 1: DNA control; lane 2–6:
Figure 11. Gel electrophoresis diagram showing the cleavage of pBR322 DNA
DNA þ complex (0.10, 0.15, 0.25, 0.45 and 0.70 mM), respectively.
incubated at 37 ꢂC for 3 h at a concentration of 0.50 mM complex with different
NaCl concentrations in 50 mM Tris–HCl buffer. Lane 1: DNA control; Lane 2–7:
10, 20, 30, 40, 50, 60 mM NaCl was added.
were subjected to molecular docking studies with B-DNA. As
shown in Figure 9a, the obtained energy-minimized docked
poses suggest that the best possible conformation of the
nickel(II) complex is inside the DNA major groove.
(chain B) forming hydrogen bond with the bond length of
2.520 Å and 1.944 Å, respectively. Furthermore, two N–H
groups in adenine (chain B) connect separately with O9 and
O10 of the ligand compound and forms two hydrogen
bonds with the bond length of 2.326 Å and 1.952 Å, respect-
ively. Another imino group of adenine (chain A) interacts
with O6 of the nickel(II) complex, forming a hydrogen bond
with the bond length of 1.930 Å. The docking results visually
demonstrate the consistency of the spectral analysis.
The docking results are presented as binding energy
(DGbinding) ꢁ4.56 kcal/mol, indicating that the nickel(II) com-
plex can reasonably bind to DNA. DGbinding
¼
DGvdWþhbþdesolv þ DGelec þ DGtotal þ DGtor – DGunb (Zheng,
Jiang, Li, Wu, & Yan, 2015), here vdW_hb_desolv energy
(DGvdWþhbþdesolv) ¼ ꢁ6.79 kcal/mol, electrostatic energy (DGelec
)
¼ ꢁ0.51 kcal/mol, total internal energy (DGtotal) ¼ ꢁ0.48 kcal/
mol, torsional energy (DGtor) ¼ 2.74 kcal/mol, unbound energy
(DGunb) ¼ ꢁ0.48 kcal/mol, showing the binding energy is
mainly dominated by the vdW_hb_desolv energy.
3.6. DNA cleavage studies
Hydrogen bonding contacts, as a special van der Waals
force, play an important role in the interaction between the
complex and DNA. As shown in Figure 9b, the interaction of
the nickel(II) complex with DNA established six hydrogen
bonds. Three acceptors are oxygen atoms of the ligand mol-
ecule, and three acceptors are oxygen atoms from phosphate
group in DNA helix chain. One hydroxyl group (O5-H5A) of
the nickel(II) complex contacts with the oxygen of phosphate
(chain A) forming hydrogen bond with the bond length of
1.907 Å. The other two hydroxyl group (O3-H3 and O2-H2) of
3.6.1. Effects of complex concentration on plasmid
DNA cleavage
The chemical nuclease activity of the nickel(II) complex has
been studied on plasmid pBR322 DNA cleavage by agarose
gel electrophoresis. Figure 10 shows the result of gel electro-
phoretic separations of plasmid pBR322 DNA induced by an
increasing concentration of complex in the absence of exter-
nal agents. With the increasing of the nickel(II) complex con-
centration, Form I (supercoiled DNA) is gradually converted
into Form II (nicked DNA) and Form III (linear DNA) (lanes
the nickel(II) complex contacts with the oxygen of phosphate 2–6). When the concentration of the complex is raised to

10
J. DONG ET AL.
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by amsacrine and other antitumor agents: A possible electron-transfer
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0.25 mM, Form I was completely absent, and the linear DNA
(Form III) was observed (lane 4). On increasing the complex
concentration, the linear DNA (Form III) increased corres-
pondingly (lanes 4–6). These results indicate that this com-
plex can efficiently hydrolytically cleave pBR322 DNA in the
absence of any reducing agents and the DNA cleavage activ-
ity is obviously complex concentration-dependent.
3.6.2. Effects of ion strength on the nickel(II) complex-
mediated DNA cleavage
The effects of ionic strength on pBR322 DNA cleavage by vary-
ing NaCl concentration were studied. As shown in Figure 11, the
process of cleavage was sensitive to the change of ionic
strength. When the ionic strength increasing (concentration of
NaCl from 10 to 60mM), the extent of DNA cleavage had height-
ened. The Form II (nicked DNA) decreased and converted to
Form III (linear DNA). These results suggested that the electro-
static interaction can contributions to the DNA cleavage reaction
in some degree (Zhu, Kong, Li, Wang, Wang, & Jin, 2010).
Haribabu, J., Jeyalakshmi, K., Arun, Y., Bhuvanesh, N. S. P., Perumal, P. T.,
& Karvembu, R. (2015). Synthesis, DNA/protein binding, molecular
docking. RSC Advances, 5(57), 46031–46049. https://doi.org/10.1039/
C5RA04498G
Hong, M., Geng, H. L., Niu, M. J., Wang, F., Li, D. C., Liu, J. F., & Yin, H. D. (2014).
Organotin(IV) complexes derived from Schiff base N’-[(1E)-(2-hydroxy-3-
methoxyphenyl)methylidene]pyridine-4-carbohydrazone: synthesis, in vitro
cytotoxicities and DNA/BSA interaction. European Journal of Medicinal
Chemistry, 86, 550–561. https://doi.org/10.1016/j.ejmech.2014.08.070
Hu, L. L., Jia, Z. Q., Tao, J., Huang, R. B., & Zheng, L. S. (2008). Synthesis,
crystal structure and magnetic properties of a mixed-valence penta-
nuclear cobalt complex. Dalton Transactions, (44), 6113–6116. https://
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Jiang, J., Yin, H. D., Wang, F. L., Han, Z., Wang, F., Cheng, S., & Hong, M.
(2013). Novel tetranuclear triarylantimony(V) complexes with ( )-man-
delic acid ligands: synthesis, characterization, in vitro cytotoxicity and
DNA binding properties. Dalton Transactions (Cambridge, England:
2003), 42(24), 8563–8566. https://doi.org/10.1039/c3dt50221j
Kondori, T., Shahraki, O., Akbarzadeh, T. N., & Aramesh-Boroujeni, Z.
(2020). Two novel bipyridine-based cobalt (II) complexes: Synthesis,
characterization, molecular docking, DNA-binding and biological
evaluation. Journal of Biomolecular Structure and Dynamics. https://
doi.org/10.1080/07391102.2020.1713893
4. Conclusion
In this paper, we have described the synthesis and characteriza-
tion of a new nickel(II) complex, [Ni(o-van-tris)2]ꢀ2H2O. Its crystal
structure was determined by X-ray crystallography. Hirshfeld
surface analysis was employed to quantify the interactions
within crystal structure. The DNA binding of the nickel(II) com-
plex examined by absorption, fluorescence and CD spectral
techniques revealed a non-intercalative interaction between the
complex and CT-DNA. Molecular docking study suggested the
nickel(II) complex bind with major groove of DNA. DNA cleavage
studies revealed that the nickel(II) complex has the ability to
cleave nucleic acids and the extent of the cleavage was found to
be concentration and ionic strength dependent.
Disclosure statement
Kong, D. M., Wang, J., Zhu, L. N., Jin, Y. W., Li, X. Z., Shen, H. X., & Mi,
H. F. (2008). Oxidative DNA cleavage by Schiff base tetraazamacrocy-
clic oxamido nickel(II) complexes. Journal of Inorganic Biochemistry,
102(4), 824–832. https://doi.org/10.1016/j.jinorgbio.2007.12.002
Lakowicz, J. R., & Weber, G. (1973). Quenching of fluorescence by oxy-
No potential conflict of interest was reported by the author(s).
Funding
gen.
A
probe for structural fluctuations in macromolecules.
Biochemistry, 12(21), 4161–4170. https://doi.org/10.1021/bi00745a020
Lee, M., Sim, K. S., & Lo, K. M. (2015). Synthesis, characterization and bio-
logical studies of diorganotin(IV) complexes with tris[(hydroxymethy-
l)aminomethane] Schiff bases. Inorganica Chimica Acta, 429, 195–208.
https://doi.org/10.1016/j.ica.2015.01.017
This project was supported by the Scientific Research Foundation of
Liaocheng University, China (No. 318011919), the Natural Science
Foundation of Shandong Province of China (No.Y2004B02) and the
National Natural Science Foundation of China (21974068).
Li, L., Dong, J., Li, J., Jing, B., & Wang, D. (2011). A ternary copper(II) complex
for supramolecular assembly with double helices: Synthesis, crystal struc-
ture, DNA-binding and DNA-cleavage properties. Transition Metal
Chemistry, 36(3), 289–295. https://doi.org/10.1007/s11243-011-9468-0
Li, Y., Li, Y. Q., Liu, X. H., Yang, Y., Lin, D., & Gao, Q. W. (2020). The syn-
thesis, characterization, DNA/protein interaction, molecular docking
and catecholase activity of two Co(II) complexes constructed from the
aroylhydrazone ligand. Journal of Molecular Structure, 1202, 127229.
https://doi.org/10.1016/j.molstruc.2019.127229
Li, Y., Li, Y. Q., Wang, N. N., Lin, D., Liu, X. H., Yang, Y., & Gao, Q. W.
(2019a). Synthesis, DNA/BSA binding studies and in vitro biological
assay of nickel(II) complexes incorporating tridentate aroylhydrazone
and triphenylphosphine ligands. Journal of Biomolecular Structure and
Dynamics, https://doi.org/10.1080/07391102.2019.1694995
ORCID
Jinming Kong
Lianzhi Li
http://orcid.org/0000-0001-5721-6513
http://orcid.org/0000-0002-8447-3803
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