Chemical Engineering Science 236 (2021) 116508

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Chemical Engineering Science

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

Molecular dynamics simulation of the formation of methane hydrates in

the presence of KHIs
Liwei Cheng a, Jinlong Cui a, Zhi Li b, Bei Liu a,⇑, Shuai Ban a,⇑, Guangjin Chen a
a
State Key Laboratory of Heavy Oil Processing, China University of Petroleum, Beijing 102249, China
b
Shandong Provincial Key Laboratory of Molecular Engineering, QiLu University of Technology (Shandong Academy of Science), Jinan 250353, China

h i g h l i g h t s

 The inhibition process of methane hydrate formation in the absence/presence of kinetic hydrate inhibitors (KHIs) were given.
 The new microscopic insights into the mechanism of KHIs on methane hydrate were present.
 The influence of KHIs on the nucleation and growth of methane hydrate was analyzed.

a r t i c l e i n f o a b s t r a c t

Article history: Poly(N-vinylpyrrolidone) (PVP) and PVP-A were selected as typical kinetic hydrate inhibitors (KHIs) to
Received 21 August 2020 simulate the inhibition processes of methane hydrate formation, where PVP-A is obtained by introducing
Received in revised form 19 January 2021 butyl ester groups into the PVP molecule. The results show that KHIs do not significantly delay the for-
Accepted 2 February 2021
mation of the first complete hydrate cage, but inhibit the nucleation of methane hydrate by retarding the
Available online 11 February 2021
formation and growth of the labile clusters and reducing the stability of newly formed hydrate cages. The
steric effect and H-bond between inhibitor molecules and the labile clusters are not the main reasons for
Keywords:
inhibiting methane hydrate nucleation. The formation of hydrate cages can be effectively inhibited by
Molecular simulation
Kinetic hydrate inhibitors
KHIs during the nucleation stage, but ineffective in the rapid growth stage. Moreover, PVP and PVP-A
Hydrate exhibit dual-functionality, i.e., disturbing H-bonding between water molecules and the movement of
Hydrate nucleation methane and water.
Ó 2021 Elsevier Ltd. All rights reserved.

1. Introduction
Gas hydrates are ice-like crystals that enclose guest molecules
in cages formed by H-bonds between water molecules (Sloan and
Koh, 2008). Serious problem can be caused by hydrate formation,
such as the blockage of oil/gas transportation pipelines. For off-
shore oil and gas pipeline transportation, this problem is a partic-
ular threat because of elevated pressure and low temperature
(Hammerschmidt, 1934; Wu et al., 2007; Eslamimanesh et al.,
2011). A traditional method to solve this problem is to inject high
concentrations of thermodynamic inhibitors (Li et al., 2006;
Mohammadi and Richon, 2010; Sun et al., 2012). This method is
effective, but costly and harmful to the environment. Another
method is to inject low dosage hydrate inhibitors (LDHIs) which
are usually injected at a dosage of 0.1–1.0 wt% and rarely affect
the boundary of the hydrate equilibrium phase. LDHIs can be
⇑ Corresponding authors.
E-mail addresses: liub@cup.edu.cn (B. Liu), banshuai@cup.edu.cn (S. Ban).
divided into two types, i.e., kinetic hydrate inhibitors (KHIs) and
anti-agglomerants (AAs). Among them, KHIs can inhibit the forma-
tion of hydrates, while AAs can impede hydrate particles from
agglomerating (Kelland, 2006; Perrin et al., 2013; Chen et al.,
2015). A number of KHIs have been commercialized and proven
to be effective (Lederhos et al., 1996; Perrin et al., 2013;
Shahnazar et al., 2018).
Although KHIs have been extensively studied by experimental
works (Kumar et al., 2008; Ajiro et al., 2010; Qin et al., 2015;
Zhang et al., 2018), a significant challenge still exists in under-
standing the mechanism of the inhibition process that is difficult
to access due to the small size and time scale. As a supplementary
method, molecular simulation is becoming increasingly important
for investigating the mechanism of clathrate hydrate nucleation.
Recently, the theoretical study performed by Kvamme et al.
(1997) showed that water molecules can build H-bonds with
oxygen atoms in poly(N-vinylpyrrolidone) (PVP) monomers, and
the monomers tend to be perpendicular to the nucleus surface.
Anderson et al. (2005) proposed the surface adsorption

https://doi.org/10.1016/j.ces.2021.116508
0009-2509/Ó 2021 Elsevier Ltd. All rights reserved.
L. Cheng, J. Cui, Z. Li et al.
mechanism, i.e., the binding of KHIs to hydrate crystals inhibits the
growth of hydrates. Moon et al. (2003) studied methane hydrate
nucleation in the presence of PVP using molecular dynamics simu-
lation methods. They found that surface adsorption is not respon-
sible for PVP. Yagasaki et al. (2015) argued that the hydrogen bond
between polyvinylcaprolactan (PVCap) and water molecules does
not contribute to the adsorption of inhibitor on the surface of
hydrates. In addition, Yagasaki et al. (2018) studied the adsorption
of KHIs on the surface of hydrate. They pointed out that the inhibi-
tion behavior of PVCap follows the Gibbs–Thomson effect.
Recently, PVP-A was obtained by introducing butyl ester groups
on PVP molecules and it was found that the inhibition effect of
PVP-A is better than that of PVP (Qin et al., 2015; Li et al., 2017).
Moreover, the gas-adsorbing mechanism, that is, inhibitors can
adsorb gas molecules and delay the movement of methane to
hydrate nuclei, thus delaying the growth of hydrates was proposed
by our group (Li et al., 2019). However, these inhibition mecha-
nisms of kinetic hydrate inhibitors are inconclusive.
To study the effect of kinetic inhibitors on the formation process
of methane hydrate, in this work, the nucleation of methane
hydrates in inhibitor-containing and inhibitor-free systems was
studied by molecular dynamics simulation. PVP and PVP-A were
chosen as the typical KHIs both of which contain polyvinyl back-
bones and pyrrolidone rings. By analyzing the process of methane
hydrate formation, our work presents microscopic insights into the
inhibition process and helps to further understand the perfor-
mance of KHIs.
2. Simulation details
Molecular dynamics simulation was performed using LAMMPS
(Plimpton, 1995). For simulation systems without inhibitors, the
initial configuration was constructed with a hydrate crystal layer
and liquid water slabs. The hydrate crystal layer was created by
3  3  4 unit cell of type sI methane hydrate crystals, and hydrate
crystals were generated according to Bernal-Fowler ice rules
(Bernal and Fowler, 1933). Each liquid water slab contains 414
water molecules. The system contains 2070 water and 288
methane molecules. For the inhibitor-containing system, the poly-
mer of the PVP chain is isotactic and contains eight monomeric
units. The PVP chain length was set according to Makogon’s con-
clusion that it is sufficient to distinguish the inhibitors when the
polymer chain length exceeds eight monomer units (Makogon,
1997). The chain length of PVP-A is set to be 4 in comparison with
the PVP model. The molecular structures of KHI molecules are
shown in Fig. 1. One polymer chain of the KHI molecule was placed
in an inhibitor-containing system. The mass concentration of KHIs
in our simulation is higher than the normal experimental dosage.
Adding more water molecules to the simulation can enhance
gas–liquid contact and shorten the hydrate nucleation time, but
dramatically increases the time required for the simulation. For
the sake of computing efficiency, we choose a higher KHI mass
Fig. 1. The molecular structures of KHIs molecules. (a) PVP and (b) PVP-A.
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Chemical Engineering Science 236 (2021) 116508
concentration than the experiment for simulation. The TIP4P-EW
force field (Jorgensen et al., 1983) was set to calculate water mole-
cules, the OPLS-AA force field (Jorgensen et al., 1996) was used to
describe methane molecules, and the CVFF force field (Dauber-
Osguthorpe et al., 2010) was used for PVP and PVP-A in line with
our previous works (Li et al., 2017; Cheng et al., 2019a). The
Lorentz-Berthelot combination rule was used to describe the
Lennard-Jones parameters of different types of atoms, except for
the Owater-Cmethane interaction using d = 3.3032 Å and e = 0.255 kc
al/mol, which was obtained by Cao et al. (2001) The bond length
and the angle of water molecules were fixed by the SHAKE algo-
rithm (Ryckaert et al., 1977). The LJ cutoff radius of the systems
was set to 9.5 Å. The electrostatic interactions were calculated
using the PPPM (Hockney and Eastwood, 1981) summation
technique.
For the procedure of molecular dynamics (MD) simulations, ini-
tial configurations were first generated and annealed by energy-
minimization. Then, a short MD simulation in the NVT ensemble
at 350 K was performed for 20 ps to relax the systems. After that,
a NPT simulation at 350 K and 3 MPa was conducted for 0.5 ns to
melt the hydrate crystals. Methane bubbles were observed at this
stage. Finally, these systems were cooled and pressurized to
hydrate forming conditions at 270 K and 20 MPa, and monitored
for nucleation. A Nosé-Hoover thermostat with a relaxation time
of 0.1 ps and pressure barostat with a relaxation time of 1 ps were
chosen. The time steps of simulation were set to be 1.0 fs.
3. Results and discussion
3.1. Effect of KHIs on methane hydrate nucleation
Fig. 2 displays the radial distribution functions (RDF) of oxygen
atoms in water at different times in different systems. The first
peak at 2.72 Å represents the distance between two H-bonded oxy-
gen atoms and the second peak at 4.5 Å corresponds to the tetra-
hedron of H-bonds. The following 3 peaks in the range of 5.5–
11 Å relate to the pentagonal rings and hexagonal rings in hydrate,
all of which increase irrespective of the presence of KHI agents. As
the simulation advances, the second and third peaks become
increasingly clear. In particular, the inhibitor-free system shows
fourth and fifth peaks at 50 ns, while fourth and fifth peaks in
the PVP and PVP-A-containing systems appeared only after
150 ns and 850 ns, respectively. This phenomenon indicates that
hydrates were formed in all systems. However, hydrate formation
in the inhibitor-free system was faster than that in the KHI-
containing systems. The PVP and PVP-A molecules are able to pro-
nouncedly delay the occurrence of the fourth and fifth peaks and
reduce the order of the system, which means that PVP and PVP-A
molecules can delay the formation of pentagonal rings and hexag-
onal rings in the systems. The pentagonal rings and hexagonal
rings are the key structures for forming hydrate cages. These
results show that PVP and PVP-A can inhibit methane hydrate cage
L. Cheng, J. Cui, Z. Li et al.
Fig. 2. The RDF of oxygen atoms in water at different times: (a) inhibitor-free
system, (b) PVP-containing system, and (c) PVP-A-containing system.
formation. Moreover, PVP-A has a better inhibitory effect on
methane hydrate formation. Our simulation results are consistent
with experimental results (Qin et al., 2015; Li et al., 2017).
Nucleation usually means that the first stable hydrate cage
appears in the gas–liquid system. To accurately trace the nucle-
ation process, the Cage identification algorithm (Jacobson et al.,
2009) was applied in our simulations to the statistics of hydrate
cages. The results in Fig. 3 show the numbers of cages varying as
a function of simulation time. For the inhibitor-free system, the
stable nucleus appears at 6.12 ns, which was considered to be
the nucleation time for methane hydrate. After that, the number
of hydrate cages increases slowly before a rapid rise at 30 ns. At
approximately 100 ns, the growth of hydrates almost stops and
the number of hydrate cages tends to stabilize. For KHI-
containing systems, it was found that the formation and decompo-
sition of hydrate cages occur frequently before the appearance of
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Chemical Engineering Science 236 (2021) 116508
Fig. 3. The evolution of the number of hydrate cages for different systems: PVP-
containing system (black line), inhibitor-free system (red line), and PVP-A-
containing system (blue line). (For interpretation of the references to color in this
figure legend, the reader is referred to the web version of this article.)
stable nuclei. This phenomenon suggests that although complete
methane hydrate cages can still be formed in the presence of
kinetic inhibitors before nucleation, the kinetic inhibitor would
significantly reduce the stability of the newly formed hydrate cage.
These hydrate crystal nuclei are unstable and thus cannot serve as
nucleation sites. Compared with the inhibitor-free system, PVP and
PVP-A molecules can significantly delay the nucleation of methane
hydrate to nucleation times of approximately122.64 ns and
751.44 ns, respectively. Upon the rapid growth phase of methane
hydrate, the growth rates of hydrate cages in inhibitor-
containing systems are almost identical to those of inhibitor-free
system. This indicates that PVP and PVP-A molecules can effec-
tively inhibit the nucleation of methane hydrate, but fail in the
rapid growth stage.
To gain insights into methane hydrate nucleation at the nanos-
cale, simulation snapshots for inhibitor-free and inhibitor-
containing systems are shown in Figs. 4–6. As shown in Fig. 4b,
the first semi-caged structure formed at 0.42 ns. The semi-caged
structure consists of multiple pentagonal rings formed by H-
bonds of water, the central space of which has not yet been occu-
pied by methane. The framework is unstable and only exists for a
few picoseconds. For the molecular snapshot at 1.96 ns illustrated
in Fig. 4c, several scattered semi-caged structures appeared, and
methane molecules were trapped inside. The hydrophobic-
hydrophilic (i.e., methane-water) interaction plays a key role in
stabilization of the pentagonal ring structure formed by water
molecules (Liu et al., 2017). It is believed that methane can
enhance the interconnection of semi-caged fragments. Subse-
quently, new semi-cage structures can be formed around the exist-
ing structure and gradually aggregate into large labile clusters by
sharing five-member or six-member rings. The growth of labile
clusters would in turn stabilize the semi-caged structures inside.
As shown in Fig. 4f, one of the semi-caged structures formed a
completely closed hydrate cage of type 512 at 2.92 ns. However,
this cage was unstable and insufficient to support the continuous
growth of hydrate nuclei and eventually decomposed after a few
picoseconds. The first stable cage of the 512 methane hydrate cage
formed at 6.12 ns. This cage links with multiple semi-caged struc-
tures by sharing pentagonal rings. Our results reveal that the com-
plete hydrate cages evolve from the semi-caged structures in labile
clusters. The size of the labile cluster has an essential effect on the
nucleation of methane hydrates.
L. Cheng, J. Cui, Z. Li et al.
Fig. 4. Snapshots of methane hydrate nucleation for the inhibitor-free system at times of (a) 0 ns, (b) 0.42 ns, (c) 1.96 ns, (d) 2.18 ns, (e) 2.92 ns, (f) 4.84 ns, (g) 5.98 ns, and (h)
6.12 ns. (H2O is shown in red, CH4 is shown in yellow, complete hydrate cages are shown in green, and red lines represent H-bonds. For clarity, hydrogen atoms of water and
methane are not plotted.) (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
As a comparison, the methane hydrate nucleation processes in
KHI-containing systems are shown in Figs. 5 and 6. For the PVP-
and PVP-A-containing systems, the first semi-caged structure
appeared at 1.18 ns and 0.46 ns, followed by multiple dispersed
semi-cage structures formed in these systems. In the PVP-
containing system, the first completely hydrate cage was observed
at 5.16 ns, while the PVP-A-containing system generated the first
completely hydrate cage at 5.36 ns. This means that KHIs did not
significantly delay the formation of the first complete methane
hydrate cage. These cages moved freely in the system and did
not share any pentagonal ring with other semi-cage structures.
As expected, these cages decomposed after only a few picoseconds,
while new semi-caged structures formed around the existing semi-
caged structure. This is the same as the situation occurring in the
pure methane-water solution system. Although labile clusters
appeared by sharing five-member or six-member rings, it is clearly
seen that PVP and PVP-A molecules could effectively delay the for-
mation and growth of labile clusters. This process was accompa-
nied by the formation and decomposition of unstable cages, in
line with the results of the Cage identification algorithm in Fig. 3.
In the PVP and PVP-A-containing systems, the reversible process
of hydrate nucleation occurred quite frequently before the nucle-
ation of methane hydrates. This is because PVP and PVP-A reduce
the stability of the newly formed hydrate cages and effectively
extend the formation time of the stable hydrate cage. Finally, the
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Chemical Engineering Science 236 (2021) 116508
PVP-containing system formed a completely closed stable 512 cage
at 128.76 ns, while the PVP-A-containing system formed that at
757.56 ns. Our results show that PVP and PVP-A molecules can
inhibit the nucleation of hydrates by retarding the formation and
growth of labile clusters and reducing the stability of newly formed
hydrate cages, and the inhibition performance of PVP-A is rela-
tively better than that of PVP. We speculate that the inhibitors
affect the movement of surrounding water and methane mole-
cules, thereby increasing the interference of water and methane
molecules on the semi-cage structure clusters and newly formed
hydrate cages.
To clarify the role of the labile cluster in methane hydrate
nucleation, the evolution of hydrates from semi-cage structure to
the complete cage is visualized in Fig. 7. New semi-cage structures
are generated around the existing semi-cage structures by sharing
pentagonal rings or hexagonal rings. In the meantime, the semi-
cage structure can form a complete hydrate cage through the
assembly of methane and water molecules. All types of hydrate
clusters can evolve into complete hydrate cages, meaning that
the size of hydrate clusters is not a determinant factor of hydrate
formation. However, the complete cages built by small hydrate
clusters are poorly stable. As shown in Fig. 7a and b, the complete
hydrate cages with the small size of hydrate clusters easily decom-
posed and transformed back to semi-cage structures. As a compar-
ison, the complete hydrate cage built by the large size of hydrate
L. Cheng, J. Cui, Z. Li et al. Chemical Engineering Science 236 (2021) 116508

Fig. 5. Snapshots of methane hydrate nucleation for the PVP-containing system at times of (a) 0 ns, (b) 1.18 ns, (c) 4.88 ns, (d) 5.16 ns, (e) 10.94 ns, (f) 37.90 ns, (g) 52.12 ns,
(h) 65.48 ns, (i) 70.36 ns, (j) 99.24 ns, (k) 115.12 ns, and (l) 128.76 ns. (H2O is shown in red, CH4 is shown in yellow, complete hydrate cages are shown in green, and red lines
represent H-bonds. Hydrogen atoms of water and methane are not plotted.) (For interpretation of the references to color in this figure legend, the reader is referred to the web
version of this article.)

clusters can promote the formation of new hydrate cages to a cer-
tain extent, as shown in Fig. 7c. This phenomenon indicates that
the large size of hydrate labile clusters contributes to the stability
of newly formed hydrate cages and facilitates the growth of
hydrate cages. In other words, large labile clusters will appear
before stable hydrate nuclei are formed in the system. By analyzing
the results of Fig. 5 and Fig. 6, PVP and PVP-A molecules could
effectively delay the formation and growth of labile clusters. It
was concluded that KHIs can inhibit hydrate nucleation by delay-
ing the formation and growth of labile clusters. Although small
hydrate labile clusters form complete hydrate cages, they are
unstable and have difficulty facilitating the hydrate growth.
In addition, the mean square displacement (MSD) of water and
methane molecules was calculated, as shown in Fig. 8. The slopes
of the MSD curves are used to evaluate the diffusion coefficient
of molecules. When the MSD curve is parallel to the X axis, the dif-
fusion coefficient of water and methane molecules would be 0 due
to the immobilization of molecules in the solid hydrate (Li et al.,
2017). According to the analysis of Fig. 4, the inhibitor-free system
formed a stable hydrate crystal nucleus at 6.12 ns. To compare the

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L. Cheng, J. Cui, Z. Li et al. Chemical Engineering Science 236 (2021) 116508

Fig. 6. Snapshots of methane hydrate nucleation for the PVP-A-containing system at times of (a) 0 ns, (b) 0.46 ns, (c) 5.36 ns, (d) 9.14 ns, (e) 13.36 ns, (f)74.8 ns, (g) 148.80 ns,
(h) 226.86 ns, (i) 469.78 ns, (j) 517.56 ns, (k) 688.08 ns, and (l) 757.56 ns. (H2O is shown in red, CH4 is shown in yellow, complete hydrate cages are shown in green, and red
lines represent H-bonds. Hydrogen atoms of water and methane are not plotted.) (For interpretation of the references to color in this figure legend, the reader is referred to
the web version of this article.)

effects of kinetic inhibitors on water and methane molecules in the
induction phase, we enlarged the MSD curves at 0–10 ns. For the
MSD of methane molecules, the MSD curve would increase rapidly
at the beginning of the simulation. This is due to the presence of
methane bubbles in the system and the migration of methane
molecules to the liquid phase. After that, the methane bubbles
are completely dissolved into the liquid phase and the slopes of
the MSD of methane molecules decrease. For the inhibitor-free sys-
tem, PVP-containing system, and PVP-A-containing system,
methane bubbles disappear at the time approximately 2 ns, 4 ns,
and 0.6 ns, respectively. After 2 ns, the slopes of the MSD curve
of methane molecules in the inhibitor-free system were smaller
than those in the inhibitor-containing systems, implying a smaller
diffusion coefficient of water and methane molecules. For the MSD
of water molecules, the slopes of the MSD curve of water molecules
in the inhibitor-free system was also smaller than those in the
inhibitor-containing systems. Our simulation results confirm that
PVP and PVP-A molecules can expedite the movement of methane
and water molecules before the methane hydrate nucleation. The
stability of clathrate structures is disturbed by violent migration

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L. Cheng, J. Cui, Z. Li et al. Chemical Engineering Science 236 (2021) 116508

Fig. 7. The evolution of hydrates from semi-cage structure to complete cage in PVP-containing system (The methane molecules in complete cage are in purple, the methane
molecules in semi-cage structure are in yellow, O in red, H in white, and blue dotted lines represent H-bonds). (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of this article.)

of molecules, thereby inhibiting the nucleation of hydrate. The
MSD curves of methane and water molecules continue to increase
with time until the free water and methane in the system are com-
pletely consumed. In addition, the MSD curves of water molecules
were still not parallel to the X axis until the end of the simulation.
This is because the water molecules in the system were not com-
pletely converted into hydrates.
During the simulation, a few labile clusters would form around
KHI molecules. Fig. 9 shows simulation snapshots of labile clusters
around PVP and PVP-A molecules before hydrate nucleation. It can
be observed that double-bond oxygen atoms of pyrrolidone rings
and ester groups build H-bonds with surrounding water molecules
due to the strong electrostatic potential between water and oxygen
atoms of KHI molecules. In particular, when labile clusters were
formed around the KHIs molecules, the KHI molecules formed H-
bonds with the adjacent semi-cage structures. The semi-cage
structures that have H-bonds with PVP and PVP-A molecules
decompose rapidly. This phenomenon suggests that the H-bonds
between inhibitor molecules and the water molecule on the
semi-cage structure cause the decomposition of the semi-cage

7
L. Cheng, J. Cui, Z. Li et al.
Fig. 8. The MSD of (a) methane and (b) water molecules in different systems.
Fig. 9. Simulation snapshots of (a) PVP and (b) PVP-A during methane hydrate
nucleation.
structure. At the same time, the inhibitor molecules would occupy
a certain space, where the steric hindrance effect affects the self-
assembly behavior of surrounding methane and water molecules,
resulting in the obstacle of forming a complete hydrate cage
around PVP and PVP-A molecules. However, the steric hindrance
effect and the H-bonds between the inhibitor molecules and the
labile cluster can only affect the arrangement of water and
methane molecules around the inhibitor rather than areas far away
from the inhibitor molecules. During the entire simulation process,
most of the decomposed semi-cage structures as well as complete
cage structures do not establish hydrogen bonds in connection
with the inhibitor molecules. These results confirm that the steric
hindrance effect and H-bonds between inhibitor molecules and the
water molecule on the labile clusters play a certain role in the
inhibition of hydrate nucleation, even though this is not the main
reason. Both PVP and PVP-A molecules have H-bonds with the
semi-cage structures through the oxygen atoms on the pyrrolidone
ring, while the ester structure on the PVP-A molecule does not
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Chemical Engineering Science 236 (2021) 116508
participate in it. This may be because the interaction energy
between the ester group and H2O is weaker than the interaction
energy between the pyrrolidone ring and H2O (Li et al., 2019),
resulting in insufficient affinity between the ester group and
semi-cage structure.
To study the influence of inhibitor molecules on surrounding
methane and water molecules, the numbers of methane and water
molecules within 1 nm of PVP and PVP-A molecules were calcu-
lated and the results are shown in Fig. 10. There are approximately
70 methane molecules around the PVP molecule before the num-
ber drops to approximately 50 upon hydrate nucleation at
220 ns. This is due to the confinement of methane molecules in
hydrates. In contrast, there are approximately 80 methane mole-
cules around the PVP-A molecule before the number drops to
approximately 50 upon hydrate nucleation at 800 ns. This phe-
nomenon shows that the PVP-A molecule with higher hydropho-
bicity has stronger interaction with methane than PVP before
hydrate formation. Meanwhile, there are approximately 500 water
molecules around the PVP and PVP-A molecules. Unlike the case of
methane molecules, the number of water molecules around the
inhibitor molecules increases with the formation of hydrates.
When methane molecules around the inhibitor molecules are
reduced, the free space is immediately occupied by water mole-
cules. Therefore, the PVP and PVP-A molecules not only build H-
bonds with surrounding water molecules, but also adsorb methane
molecules directly. The aggregation of methane molecules by inhi-
bitor molecules constrains the movement of methane molecules
and thus interferes with the arrangement of methane hydrate
structures.
3.2. Effect of KHIs on methane hydrate growth
During the period of hydrate growth, water and methane mole-
cules assemble to form hydrate cages around the existing methane
hydrate cages. Typical snapshots of methane hydrate growth for
the inhibitor-free system are shown in Fig. 11. It can be seen that
water and methane molecules self-assembled on the surface of
the existing hydrate cages and formed new hydrate cages. The
hydrate cages grew rapidly as the simulation progresses, and four
different types of hydrate cages appeared in the inhibitor-free sys-
tem. The 512, 51262, 51263, and 51264 cages were distinguished with
different color. Different types of cages can share pentagonal or
hexagonal rings to facilitate the growth of hydrate cages, while
amorphous clusters containing clathrate hydrates may also form.
These simulation results are consistent with the reported studies
on methane nucleation (Walsh et al., 2009; Jiménez-Ángeles and
L. Cheng, J. Cui, Z. Li et al. Chemical Engineering Science 236 (2021) 116508

Fig. 10. Variations in the number of methane and water molecules within 1 nm of the (a) PVP and (b) PVP-A molecules.

Fig. 11. Snapshots of methane hydrate growth of the inhibitor-free system at times of (a) 6.12 ns, (b) 20 ns, (c) 25 ns, (d) 50 ns, (e) 75 ns, and (f) 100 ns. (512 cages are in green,
51262 cages are in blue, 51263 cages are in purple, and 51264 cages are in orange.) (For interpretation of the references to color in this figure legend, the reader is referred to the
web version of this article.)

Firoozabadi, 2014). The existence of methane hydrate cages as the the decomposition of cages and the formation of new cages. This
initiators of the new phase accelerates the formation of methane is because the newly formed hydrate cages still have the risk of
hydrates. However, the formed hydrate cages are not absolutely being disrupted by the surrounding water and methane molecules.
stable, and the hydrate growth process is also accompanied by In addition, 512 cages and 51262 cages account for the majority of

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L. Cheng, J. Cui, Z. Li et al. Chemical Engineering Science 236 (2021) 116508

the system. This is consistent with the description of the character-
istics of methane hydrate (Sloan and Koh, 2008).
The process of methane hydrate growth with PVP and PVP-A are
shown in Figs. 12 and 13. Water and methane molecules away
from inhibitor molecules start to arrange and form new methane
hydrate cages in the vicinity of existing methane hydrate cages.
The hydrate cages grew rapidly as the simulation progresses. The
512, 51262, 51263, and 51264 cages were distinguished with different
color. We found that the number of 51264 cages in the PVP-
containing system is less than that in the PVP-A containing system.
This phenomenon indicates that, comparing with PVP, PVP-A can
slightly promote the formation of sII hydrate. However, for the
PVP and PVP-A containing systems, the 512 and 51262 cages always
account for the majority of the systems, while the 51264 cages are
very few. It is means that these systems are still dominated by sI
hydrate, and PVP and PVP-A molecules cannot change the prefer-
ence of methane hydrate formation. As shown in Figs. 12 and 13,
in the early stage of hydrate growth, the adjacent region of the
kinetic inhibitor molecules does not form complete hydrate clath-
rate structure. The PVP and PVP-A molecules do not immediately
attach onto the surface of methane hydrates, but flow freely in
the aqueous phase. The inhibitor molecules still interfere with
the self-assembly of surrounding methane and water molecules.
Once the amorphous hydrate reaches a certain size, inhibitor mole-
cules adsorb on the surface of the hydrate nucleus. Combined with
the results of Fig. 3, when PVP and PVP-A are adsorbed to the sur-
face of the hydrate crystal nucleus, the number of cages in the sys-
tem is 34 and 91, respectively. This is due to the difference in the
molecular structure of KHIs and the adsorption capacity of hydrate
nuclei for different inhibitors. However, methane hydrate has
already entered a rapid growth stage, and the inhibitory effect of
kinetic inhibitors on the formation of methane hydrate is invali-
dated. A part of the functional groups of the polymer chain was
embedded in the semi-caged structure, while the other part was
still free in the aqueous phase. In addition, it could be seen that
the growth rate of hydrates around the inhibitor molecules is
slower than elsewhere. This is because the PVP and PVP-A mole-
cules form steric hindrance and interfere with the self-assembly
behavior of surrounding methane and water molecules. Our simu-
lation indicates that the role of PVP and PVP-A in the hydrate
growth process could be distinguished into two aspects. In the
early stage of hydrate growth, inhibitor molecules flow freely in
the aqueous phase and do not contact hydrate cages directly. Like
the nucleation stage, PVP and PVP-A can delay hydrate formation

Fig. 12. Snapshots of the methane hydrate growth process for the PVP containing system at times of (a) 128.76 ns, (b) 130.28 ns, (c) 157.10 ns, (d) 167.80 ns, (e) 173.52 ns,
and (f) 268.34 ns. (H2O are shown in red, CH4 are in yellow, 512 cages are in green, 51262 cages are in blue, 51263 cages are in purple, and 51264 cages are in orange. Hydrogen
atoms of water and methane are not plotted.) (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

10
L. Cheng, J. Cui, Z. Li et al. Chemical Engineering Science 236 (2021) 116508

Fig. 13. Snapshots of the methane hydrate growth process for the PVP-A containing system at times of (a) 757.56 ns, (b) 757.70 ns, (c) 759.34 ns, (d) 771.86 ns, (e) 853.88 ns,
and (f) 915.80 ns. (H2O are shown in red, CH4 are in yellow, 512 cages are in green, 51262 cages are in blue, 51263 cages are in purple, and 51264 cages are in orange. Hydrogen
atoms of water and methane are not plotted.) (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

by increasing the instability of the surrounding newly hydrate

cages. In the following rapid growth stage of hydrate, PVP and
PVP-A molecules adsorb to the surface of the hydrate nucleus
and become deactivated.
Our simulations have shown that when the amorphous hydrate
reaches a certain size, PVP and PVP-A are adsorbed on the surface
of crystals. However, this result is inconsistent with previous
research showing that PVP does not adsorb on the hydrate nucleus
but remains away from the surface of hydrate crystals at least 5–
10 Å (Moon et al., 2007). The snapshots in Fig. 14 show that part
of the functional group of PVP and PVP-A molecules was embedded
in the semi-cage structure. The inhibitor molecules are connected
with the semi-cage structures via H-bonds, which disturb the H-
bonds between the water molecules. Once hydrate cages start to
rapidly grow on a large scale, inhibitor molecules become unable
to impede the growth of the hydrate cage anymore. However, it
is still difficult to locally form complete hydrate cages around the Fig. 14. Locally enlarged (a) PVP and (b) PVP-A molecules during the methane
inhibitor molecules in that the H-bonds disturb the H-bonds of sur- hydrate growth stage.
rounding water molecules. In the meantime, the steric hindrance
by PVP and PVP-A molecules decreases the contact of the hydrate Fig. 14, the PVP molecule was in closer contact with the surface
nucleus with the surrounding water and methane molecules and of the hydrate crystal nucleus, and the surface curvature of the
increases the curvature of the hydrate surface. As shown in hydrate crystal nucleus was significantly changed. In contrast,
11
L. Cheng, J. Cui, Z. Li et al.
the PVP-A molecule has only one ester group in direct contact with
the surface of the hydrate crystal nucleus and the surface of the
hydrate crystal nucleus is smoother. This is due to the Gibbs-
Thomson effect, in which the growth rate of the concave surface
is much lower than that of the flat surface (Raymond and
Devries, 1977; Nada and Furukawa, 2012; Yagasaki et al., 2018).
The numbers of different types of cages were computed and are
shown in Fig. 15. The unit cell of sI hydrate contains 512 cages and
51262 cages, and the unit cell of sII hydrate contains 512 cages and
51264 cages. The large cage of 51262 could increase the stability of
the small cage 512. The cage of 51263 is the intermediate linking
of sI and sII hydrates (Walsh et al., 2009; Jiménez-Ángeles and
Firoozabadi, 2014). The large 51264 cages are only found in sII
hydrate (Sloan and Koh, 2008). For pure methane hydrate, sI
hydrate has a thermodynamically stable structure, while sII
hydrate has a the kinetically stable structure (Walsh et al., 2009).
Methane-water solution system facilitates sI hydrate. Our simula-
tions show that 512 cages always dominate in all cases, followed by
51262 cages, while 51264 cages are the least common. It is clearly
seen that the population of sI hydrate is independent of the exis-
tence of PVP and PVP-A agents. Although inhibitors can delay the
formation of methane hydrate, they do not affect the type of
hydrate cages formed. This result is different from our previous
research showing that PVP and PVP-A can promote the formation
of sII hydrate under high subcooling conditions (Cheng et al.,
Fig. 15. The numbers of 512cages,51262 cages, 51263cages, and 51264cages versus time for the (a) inhibitor-free system, (b) PVP-containing system and (c) PVP-A-containing
system.
12
Chemical Engineering Science 236 (2021) 116508
2019b). This can be explained by the fact that KHIs can transform
the system from thermodynamically favored to kinetically favored
under high subcooling conditions.
4. Conclusions
The effects of PVP and PVP-A on the formation of methane
hydrate were studied by molecular dynamics simulation. Our
results show that PVP and PVP-A can effectively delay the nucle-
ation of hydrate, but rarely change the types of cages formed.
PVP-A has a better inhibitory effect on hydrate formation than
PVP. By analyzing the processes of methane hydrate formation, it
was found that the size of the labile cluster plays a vital role in
the methane hydrate nucleation process. KHIs will not significantly
delay the formation of the first complete methane hydrate cage but
can inhibit the nucleation of hydrate by retarding the formation
and growth of the labile clusters and reducing the stability of
newly formed hydrate cages. The steric effect and H-bond between
inhibitor molecules and labile clusters are not the main reasons for
inhibiting hydrate nucleation. Additionally, the KHI molecules
shows dual-functions, i.e., disturbing H-bonds between water
molecules and the movement of methane and water molecules.
The stabilization of clathrate structures could be interfered with
by the violent movement of methane and water molecules, thereby
impeding the formation of methane hydrate. Our simulation shows
L. Cheng, J. Cui, Z. Li et al.
the complex interactions between methane, water, and KHIs at
various stages, and provides microscopic insights into the inhibi-
tion process of KHIs on methane hydrate formation.
CRediT authorship contribution statement
Liwei Cheng: Conceptualization, Methodology, Investigation.
Jinlong Cui: Software, Data curation. Zhi Li: Visualization, Investi-
gation. Bei Liu: Supervision, Validation. Shuai Ban: Supervision.
Guangjin Chen: Supervision.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
The financial support received from the National Natural
Science Foundation of China (21776301) and the Strategic Cooper-
ation Technology Projects of CNPC and CUPB(ZLZX2020-04) are
gratefully acknowledged.
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