Molecular Dynamic Simulation of Gemcitabine in Rigid MIL-127(Fe)

Manipol, Erwin T.
Department of Biochemistry, Faculty of Pharmacy, University of Santo Tomas, España Manila, Philippines

ABSTRACT
The use of metal-organic frameworks (MOFs) have emerged as a promising platform for drug delivery due
to its high porosity, high drug loadings, biodegradability, and versatile functionality. In this study, MIL-
127(Fe), a non-toxic porous iron (III)-based metal–organic framework, was used as the carrier for the anti-
cancer chemotherapy drug, gemcitabine. Molecular dynamics simulations were performed to study the
adsorption of 20 gemcitabine molecules inside a 2x2x2 unit cell of rigid MIL-127(Fe) framework. The
force field parameters were obtained from literature and ArgusLab calculations. Radial distribution
functions (RDFs) show that the gemcitabine molecules reside nearest to water and hydroxide molecules.
Also, it is observed that the RDFs of gemcitabine to organic linkers are shorter compared to that with the
metal clusters. Lastly, the high diffusion coefficient of the drug averaged to be 1.5057 x 10-11 m2/s is not
validated in the simulation of the rigid framework.
INTRODUCTION
Metal-organic frameworks (MOFs) are porous apertures of the channels which makes it a good
coordination polymers built from metal oxide candidate for drug encapsulation application.
clusters and organic linkers. MOFs are known to
have good permeability, high void volume, and
effective large surface area with well-defined Fe3O metal cluster
alterable cavities of uniform size. They are also
stable over a wide range of temperature and
pressure which make them suitable for a wide
range of potential applications. 3,3′,5,5′-
azobenzenetetracarboxylate
However, one of the main drawback of MOFs
is its instability towards moisture which leads to
Figure 1. MIL-127 (Fe) framework and its two
the material’s hydrolysis. According to Chevreau
major components
et al. (2015), in their study on the synthesis of the
biocompatible and highly stable MIL-127 (Fe), As reported by Bernini, M. et al. (2014),
synthesizing MOFs on the basis of high valence toxicity and the daily requirement of the metal are
metals such as tri- (Fe3+, Cr3+) or tetra-valent the two factors that are critical in proposing a
cations (Ti4+, Zr4+) will overcome the instability novel drug-carrier system. Toxicity is
of the MOFs. determined based on the median lethal dose
In line with this, Material of Institut Lavoisier- parameter, LD50. It is used as a general indicator
127 (MIL-127) composed of trimers of iron (III) of a substance's acute toxicity which is defined as
and 3,3′,5,5′-azobenzenetetracarboxylate anions the amount of a compound that kills half the
is to be used in this simulation for drug members of a tested population after a specific
encapsulation of Gemcitabine. MIL-127(Fe) is a test duration. Moreover, the daily requirement is
stable framework with large windows/pores and useful in quantifying the biocompatibility of the
it contains two types of pores, an accessible proposed drug-carrier system.
channel system of varying size and cages of Table 1. Oral LD50 in rats and daily
around 10 Å diameter accessible through requirements in humans of selected metals
Metal LD50 (g/kg) Daily dose (mg)
 Zr 4.1 0.05 of the MIL-127(Fe) model were grouped and
Ti 25 0.8 renamed based on the atom type using Discovery
Cu 0.025 2 Studio.
Mn 1.5 5
Fe 0.45 15 II. Docking of Gemcitabine
Zn 0.35 15 The MIL-127(Fe) framework was set as the
Mg 8.1 350 binding site for the gemcitabine molecules for the
Ca 1.0 1000 molecular docking. Monte Carlo was then
performed in ArgusLab to generate random poses
Among the metals, shown in table 1, Iron is of the gemcitabine in the framework. A total of
the only high valence metal which shows a 126 poses of gemcitabine with the lowest energy
considerable LD50 of 0.45g/kg and a daily potentials were produced. These were then saved
requirement of 15mg thus it is feasible to be used and all overlapping poses were checked and
as a drug-carrier system for this study. removed individually until no overlapping
molecules were observed. Twenty of the
gemcitabine molecules with the lowest energy
remained and were used for the simulation run.
The GUI of the Java software was then used to
shift the center of the framework containing the
20 gemcitabine towards the origin. The lattice
and the Config file were also made using the same
Figure 2. Structure of Gemcitabine software.
III. Molecular Dynamics
Gemcitabine is anti-cancer chemotherapy
A. Force Field Parameters
drug and is classified as antimetabolite. It works
by preventing certain proteins from being made The MIL-127(Fe) framework was set as a
that are necessary for tumor growth, specifically rigid model for all simulations so only the
it kills cancer cells by replacing one of the nonbonded potentials became significant. On the
building blocks of nucleic acids, cytidine, during other hand, the intramolecular potentials of
DNA replication. This process arrests tumor gemcitabine were obtained from UFF energy
growth since the new nucleosides cannot be calculations in ArgusLab while all the
attached to the "faulty" nucleoside, resulting in intermolecular potentials were taken from
apoptosis. Universal Force Field (UFF) data (Rappe et al.,
1992).
The main objectives of this simulation is to
determine the structural properties of Intramolecular Potential
gemcitabine inside of the framework and the
a.) Bond potentials: Harmonic bond (harm)
adsorption coefficient.
𝑘
𝑈(𝑟𝑖𝑗 ) = (𝑟𝑖𝑗 − 𝑟𝑜 )2
METHODOLOGY 2
b.) Valence Angle Potentials: Harmonic
I. MIL-127(Fe) and Gemcitabine Models (harm)
The MIL-127(Fe) model was obtained from 𝑘
𝑈(𝜃𝑗𝑖𝑘 ) = (𝜃𝑗𝑖𝑘 − 𝜃𝑜 )2
X-ray Diffraction Data while the drug 2
Gemcitabine (C9H11F2N3O4) was obtained c.) Dihedral Angle Potentials: Cosine
from the PubChem database (CID of 60750) with potential: (cos)
a molecular weight of 263.201 g/mol. The atoms
 𝑈(∅𝑖𝑗𝑘𝑛 ) = 𝐴[1 + cos(𝑚∅𝑖𝑗𝑘𝑛 − 𝛿)] 2.20 with a time step of 0.001 ps and has a total
of 1,400,000 steps; the first 400,000 steps run of
Intermolecular Potential the simulation was for equilibration while another
a.) Van der Waals Potentials: Lennard-Jones 1,000,000 steps was used for the analysis.
(lj) RESULTS
12 6
𝜎 𝜎 I. Structural properties
𝑈(𝑟𝑖𝑗 ) = 4𝜖 [( ) −( ) ]
𝑟𝑖𝑗 𝑟𝑖𝑗
Radial Distribution Functions (RDF)
B. Simulation Control Parameters
The RDF involving the most important
Molecular Dynamic simulations was
anchoring points of the adsorbents, the organic
employed to calculate the diffusion coefficient
linkers and metal clusters, are presented. The
and radial distribution functions of gemcitabine
organic linker is represented as NN and HC while
in MIL-127(Fe). The framework used has 8
FeO and OFe is used to represent the metal
(2x2x2) unit cells of MIL-127(Fe) while the
cluster. The radial distribution functions, RDF,
lattice has a dimension of 87.946x87.946x87.946
were obtained from a molecular dynamic
Angstroms at a fixed temperature of 298.45K.
simulation of gemcitabine on MIL-127(Fe) at
The simulation run was done using DL_POLY
298.45 K.

Figure 3. RDF shows the interactions involving the fluorine atoms of gemcitabine and the MIL-127(Fe)
framework. The radial distance between fluorine and the organic linkers (NN and HC) are shorter than
that of fluorine and the metal clusters (FeO and OFe). Additionally, the fluorine atoms are nearer to HC
because of the hydrogen bonding between the electronegative fluorine and HC of the organic linker.
Figure 4. Illustration of RDFs between Fluorine of Gemcitabine and atoms of MIL-127 (Fe) framework

Figure 5. RDF shows the interactions involving the nitrogen atoms of gemcitabine and the MIL-127(Fe)
framework. The radial distance between fluorine and the organic linkers (NN and HC) are shorter than
that of fluorine and the metal clusters (FeO and OFe).
Figure 6. Illustration of RDFs between Nitrogen of Gemcitabine and atoms of MIL-127 (Fe) framework

Figure 7. RDF shows the interactions involving the oxygen atoms of gemcitabine and the MIL-127(Fe)
framework. The radial distance between fluorine and the organic linkers (NN and HC) are shorter than
that of fluorine and the metal clusters (FeO and OFe).
Figure 8. Illustration of RDFs between Oxygen of Gemcitabine and atoms of MIL-127 (Fe) framework
Figure 9. RDF shows the interactions involving the atoms of gemcitabine (F, N and O) with water and
hydroxide of MIL-127(Fe) framework. The radial distance of gemcitabine with water and hydroxide are
much shorter than the organic linker and metal cluster. These RDFs show the hydrogen bonding
interaction of gemcitabine functional groups (-NH2, -OH, -F2) with water and hydroxide molecules of the
framework.

Figure 10. Illustration of Gemcitabine configuration in one unit cell of MIL-127 (Fe) framework

II. Dynamical properties CONCLUSION

From the output, the diffusion coefficient of
the drug is obtained to be 1.5057 x 10-11 m2/s. The
individual diffusion coefficient of each atom is
shown in table 2. However, the high coefficients
are not validated by the simulation. The drugs are
not diffusing out of the initial unit cell which may
be due to the rigid structure of the MIL-127(Fe).
Table 2. Approximate 3D Diffusion Coefficient
of the Gemcitabine Atoms
Atom Diffusion coefficients (m2/s)
F 1.7456 x 10-11
O 1.5447 x 10-11
N 1.6991 x 10-11
C 1.1510 x 10-11
H 1.6853 x 10-11
The RDF results show that the gemcitabine
molecules reside near the atoms of the organic
linkers, represented by NN and HC, and are found
farther from the metal clusters, represented by
FeO and OFe. However, the water and hydroxide
are observed to have the shortest distance among
the RDFs which indicates that gemcitabine drugs
are highly hydrophilic. Also, the polar functional
groups of gemcitabine are found to protrude
towards the vertices containing the metal clusters
which show the electrostatic interaction of the
metals with the drug.
Moreover, the high diffusion coefficients are
not proven by the simulation. This can be made
better by using a flexible MIL-127(Fe) to account
for the diffusion coefficients.
REFERENCES
[1] Chevreau, H., Permyakova, A., Nouar, F., Fabry,
P., Livage, C., Ragon, F., . . . Horcajada, P. (2015).
Synthesis of the biocompatible and highly stable
MIL-127(Fe): from large scale synthesis to particle
size control. CrystEngComm, 2016(18), 4094th ser.
doi: 10.1039/c5ce01864a

[2] Gemcitabine. (n.d.). Retrieved July 26, 2017,

from https://www.drugbank.ca/drugs/DB00441

[3] Pongsajanukul, P., Chokbunpiam, T., Fritzsche,

S., Assabumrungrat, S., & Parasuk, V. (May 23,
2017). Computational calculation of carbon dioxide
capture in Metal Organic Framework. Retrieved July
26, 2017, from
https://ppcconference.files.wordpress.com/2017/05/p
avee.pdf

[4] Bernini, M. C., Fairen-Jimenez, D., Pasinetti, M.,

Ramirez-Pastor, A. J., & Snurr, R. Q. (2013).
Screening of bio-compatible metal–organic
frameworks as potential drug carriers using Monte
Carlo simulations. J. Mater. Chem. B, 2014(2), 766th
ser. doi: 10.1039/c3tb21328e

[5] Rappe, A. K., Casewit, C. J., Colwell, K. S.,

Goddard, W. A., III, & Skiff, W. M. (1992). UFF, a
Full Periodic Table Force Field for Molecular
Mechanics and Molecular Dynamics Simulations. J.
Am. Chem. Soc, 114(25), 10024-10035. Retrieved
July 26, 2017.
 APPENDIX

Table 1. MIL-127(Fe) framework atoms groups, molecular weight, partial charges and number of atoms
ATOMS 6000
OFe 15.9994 -0.246 64
FeO 55.845 0.861 192
OD 15.9994 -0.47 64
HD 1.0079 0.332 64
OW 15.9994 -0.743 128
HW 1.0079 0.319 256
NN 14.0067 -0.22 312
CN 12.0107 0.189 312
CH 12.0107 -0.105 936
HC 1.0079 0.178 936
CC 12.0107 -0.021 624
CO 12.0107 0.608 624
OC 15.9994 -0.47 1008
OH 15.9994 -0.623 240
HO 1.0079 0.296 240

Table 2. Gemcitabine atoms, molecular weight, partial charges and number of atoms

ATOMS 29
F 18.9984032 -0.534 1
F 18.9984032 -0.577 1
O 15.9994 -0.608 1
O 15.9994 -0.636 1
O 15.9994 -0.634 1
O 15.9994 -0.415 1
N 14.0067 -0.38 1
N 14.0067 -0.248 1
N 14.0067 -0.611 1
C 12.01115 0.138 1
C 12.01115 0.75 1
C 12.01115 0.058 1
C 12.01115 0.299 1
C 12.01115 0.011 1
C 12.01115 0.024 1
C 12.01115 0.674 1
C 12.01115 -0.077 1
C 12.01115 0.297 1
H 1.00797 0.145 1
 H 1.00797 0.217 1
H 1.00797 0.209 1
H 1.00797 0.133 1
H 1.00797 0.194 1
H 1.00797 0.388 1
H 1.00797 0.133 1
H 1.00797 0.396 1
H 1.00797 0.12 1
H 1.00797 0.25 1
H 1.00797 0.284 1

Table 3. UFF Bond Parameters of Gemcitabine

BONDS 30
harm 1 11 347.860013 1.46848
harm 2 11 347.860013 1.46848
harm 3 12 492.984516 1.436155
harm 3 13 492.984516 1.436155
harm 4 10 492.984516 1.436155
harm 4 24 492.252805 1.033746
harm 5 14 492.984516 1.436155
harm 5 26 492.252805 1.033746
harm 6 16 523.501065 1.407689
harm 7 13 516.953249 1.461925
harm 7 15 646.835551 1.356681
harm 7 16 646.835551 1.356681
harm 8 16 646.835551 1.356681
harm 8 18 646.835551 1.356681
harm 9 18 666.232827 1.343384
harm 9 28 521.768517 1.048529
harm 9 29 521.768517 1.048529
harm 10 11 349.799987 1.514
harm 10 12 349.799987 1.514
harm 10 19 328.22623 1.112599
harm 11 13 349.799987 1.514
harm 12 14 349.799987 1.514
harm 12 20 328.22623 1.112599
harm 13 21 328.22623 1.112599
harm 14 22 328.22623 1.112599
harm 14 23 328.22623 1.112599
harm 15 17 462.660461 1.379256
harm 15 25 354.325486 1.084582
harm 17 18 462.660461 1.379256
 harm 17 27 354.325486 1.084582

Table 4. UFF Angle Parameters of Gemcitabine

ANGLES 52
harm 1 11 2 193.303511 109.47
harm 1 11 10 203.32938 109.47
harm 1 11 13 203.32938 109.47
harm 2 11 10 203.32938 109.47
harm 2 11 13 203.32938 109.47
harm 12 3 13 284.86441 104.51
harm 3 12 10 278.259153 109.47
harm 3 12 14 278.259153 109.47
harm 3 12 20 156.116442 109.47
harm 3 13 7 391.007062 109.47
harm 3 13 11 278.259153 109.47
harm 3 13 21 156.116442 109.47
harm 10 4 24 157.363455 104.51
harm 4 10 11 278.259153 109.47
harm 4 10 12 278.259153 109.47
harm 4 10 19 156.116442 109.47
harm 14 5 26 157.363455 104.51
harm 5 14 12 278.259153 109.47
harm 5 14 22 156.116442 109.47
harm 5 14 23 156.116442 109.47
harm 6 16 7 353.858227 120
harm 6 16 8 353.858227 120
harm 13 7 15 208.281355 120
harm 13 7 16 208.281355 120
harm 7 13 11 300.071623 109.47
harm 7 13 21 166.826772 109.47
harm 15 7 16 233.893264 120
harm 7 15 17 303.537949 120
harm 7 15 25 156.569278 120
harm 7 16 8 414.072275 120
harm 16 8 18 233.893264 120
harm 8 18 9 420.206471 120
harm 8 18 17 303.537949 120
harm 18 9 28 124.657989 120
harm 18 9 29 124.657989 120
harm 9 18 17 307.964574 120
harm 28 9 29 70.257681 120
harm 11 10 12 214.211821 109.47
 harm 11 10 19 116.98499 109.47
harm 10 11 13 214.211821 109.47
harm 12 10 19 116.98499 109.47
harm 10 12 14 214.211821 109.47
harm 10 12 20 116.98499 109.47
harm 11 13 21 116.98499 109.47
harm 14 12 20 116.98499 109.47
harm 12 14 22 116.98499 109.47
harm 12 14 23 116.98499 109.47
harm 22 14 23 74.849522 109.47
harm 17 15 25 114.188575 120
harm 15 17 18 222.595017 120
harm 15 17 27 114.188575 120
harm 18 17 27 114.188575 120

Table 5. UFF Torsion Angle Parameters of Gemcitabine

DIHEDRALS 78
cos 1 11 10 4 0.235444 180 3
cos 1 11 10 12 0.235444 180 3
cos 1 11 10 19 0.235444 180 3
cos 1 11 13 3 0.235444 180 3
cos 1 11 13 7 0.235444 180 3
cos 1 11 13 21 0.235444 180 3
cos 2 11 10 4 0.235444 180 3
cos 2 11 10 12 0.235444 180 3
cos 2 11 10 19 0.235444 180 3
cos 2 11 13 3 0.235444 180 3
cos 2 11 13 7 0.235444 180 3
cos 2 11 13 21 0.235444 180 3
cos 10 12 3 13 0.0651 180 3
cos 14 12 3 13 0.0651 180 3
cos 20 12 3 13 0.0651 180 3
cos 12 3 13 7 0.0651 180 3
cos 12 3 13 11 0.0651 180 3
cos 12 3 13 21 0.0651 180 3
cos 3 12 10 4 0.235444 180 3
cos 3 12 10 11 0.235444 180 3
cos 3 12 10 19 0.235444 180 3
cos 3 12 14 5 0.235444 180 3
cos 3 12 14 22 0.235444 180 3
cos 3 12 14 23 0.235444 180 3
cos 3 13 7 15 0.333333 180 3
cos 3 13 7 16 0.333333 180 3
cos 3 13 11 10 0.235444 180 3
cos 11 10 4 24 0.0651 180 3
cos 12 10 4 24 0.0651 180 3
cos 19 10 4 24 0.0651 180 3
cos 4 10 11 13 0.235444 180 3
cos 4 10 12 14 0.235444 180 3
cos 4 10 12 20 0.235444 180 3
cos 12 14 5 26 0.0651 180 3
cos 22 14 5 26 0.0651 180 3
cos 23 14 5 26 0.0651 180 3
cos 5 14 12 10 0.235444 180 3
cos 5 14 12 20 0.235444 180 3
cos 6 16 7 13 6.73711 180 2
cos 6 16 7 15 6.73711 180 2
cos 6 16 8 18 13.474221 180 2
cos 11 13 7 15 0.333333 180 3
cos 21 13 7 15 0.333333 180 3
cos 13 7 15 17 6.73711 180 2
cos 13 7 15 25 6.73711 180 2
cos 11 13 7 16 0.333333 180 3
cos 21 13 7 16 0.333333 180 3
cos 13 7 16 8 6.73711 180 2
cos 7 13 11 10 0.235444 180 3
cos 17 15 7 16 6.73711 180 2
cos 25 15 7 16 6.73711 180 2
cos 15 7 16 8 6.73711 180 2
cos 7 15 17 18 6.73711 180 2
cos 7 15 17 27 6.73711 180 2
cos 7 16 8 18 13.474221 180 2
cos 16 8 18 9 13.474221 180 2
cos 16 8 18 17 13.474221 180 2
cos 8 18 9 28 6.73711 180 2
cos 8 18 9 29 6.73711 180 2
cos 8 18 17 15 6.73711 180 2
cos 8 18 17 27 6.73711 180 2
cos 17 18 9 28 6.73711 180 2
cos 17 18 9 29 6.73711 180 2
cos 9 18 17 15 6.73711 180 2
cos 9 18 17 27 6.73711 180 2
cos 13 11 10 12 0.235444 180 3
 cos 11 10 12 14 0.235444 180 3
cos 11 10 12 20 0.235444 180 3
cos 13 11 10 19 0.235444 180 3
cos 10 11 13 21 0.235444 180 3
cos 14 12 10 19 0.235444 180 3
cos 20 12 10 19 0.235444 180 3
cos 10 12 14 22 0.235444 180 3
cos 10 12 14 23 0.235444 180 3
cos 22 14 12 20 0.235444 180 3
cos 23 14 12 20 0.235444 180 3
cos 18 17 15 25 6.73711 180 2
cos 27 17 15 25 6.73711 180 2

Table 6. Nonbonded potentials between the atoms of MIL-127(Fe) and atoms of Gemcitabine
VDW 99
OFe F 0.055 3.432
OFe O 0.06 3.5
OFe N 0.064 3.58
OFe C 0.079 3.676
OFe H 0.051 3.193
OFe OW 0.06 3.5
FeO F 0.025 3.138
FeO O 0.028 3.206
FeO N 0.03 3.286
FeO C 0.037 3.382
FeO H 0.024 2.899
FeO OW 0.028 3.206
OD F 0.055 3.432
OD O 0.06 3.5
OD N 0.064 3.58
OD C 0.079 3.676
OD H 0.051 3.193
OD OW 0.06 3.5
OW F 0.055 3.432
OW O 0.06 3.5
OW N 0.064 3.58
OW C 0.079 3.676
OW H 0.051 3.193
HW F 0.047 3.125
HW O 0.051 3.193
HW N 0.055 3.273
HW C 0.068 3.369
HW H 0.044 2.886
HW OW 0.051 3.193
NN F 0.059 3.512
NN O 0.064 3.58
NN N 0.069 3.66
NN C 0.085 3.756
NN H 0.055 3.273
NN OW 0.064 3.58
CN F 0.072 3.608
CN O 0.079 3.676
CN N 0.085 3.756
CN C 0.105 3.851
CN H 0.068 3.369
CN OW 0.079 3.676
CH F 0.072 3.608
CH O 0.079 3.676
CH N 0.085 3.756
CH C 0.105 3.851
CH H 0.068 3.369
CH OW 0.079 3.676
HC F 0.047 3.125
HC O 0.051 3.193
HC N 0.055 3.273
HC C 0.068 3.369
HC H 0.044 2.886
HC OW 0.051 3.193
CC F 0.072 3.608
CC O 0.079 3.676
CC N 0.085 3.756
CC C 0.105 3.851
CC H 0.068 3.369
CC OW 0.079 3.676
CO F 0.072 3.608
CO O 0.079 3.676
CO N 0.085 3.756
CO C 0.105 3.851
CO H 0.068 3.369
CO OW 0.079 3.676
OC F 0.055 3.432
OC O 0.06 3.5
OC N 0.064 3.58
 OC C 0.079 3.676
OC H 0.051 3.193
OC OW 0.06 3.5
OH F 0.055 3.432
OH O 0.06 3.5
OH N 0.064 3.58
OH C 0.079 3.676
OH H 0.051 3.193
OH OW 0.06 3.5
HO F 0.047 3.125
HO O 0.051 3.193
HO N 0.055 3.273
HO C 0.068 3.369
HO H 0.044 2.886
HO OW 0.051 3.193
F F 0.05 3.364
F O 0.055 3.432
F N 0.059 3.512
F C 0.072 3.608
F H 0.047 3.125
O O 0.06 3.5
O N 0.064 3.58
O C 0.079 3.676
O H 0.051 3.193
N N 0.069 3.66
N C 0.085 3.756
N H 0.055 3.273
C C 0.105 3.851
C H 0.068 3.369
H H 0.044 2.886
OW OW 0.06 3.5

Table 7. Control conditions of the Molecular Dynamic Simulation

temperature 298.45
pressure 0
ensemble nvt ber 0.1

steps 1400000
equilibration 400000
multiple step 1
scale 2
print 100
stack 200
stats 200

traj 1 1000 1

timestep 0.001
cutoff 15
delr width 1
rvdw cutoff 12
spme precision 1.00E-05