Journal of Molecular Liquids 262 (2018) 451–459

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Journal of Molecular Liquids

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

Investigation of the influence of b-cyclodextrin on cholesterol

lodgement — A molecular dynamics simulation study
Damian Makieła, Iwona Janus-Zygmunt, Krzysztof Górny, Zygmunt Gburski*
University of Silesia in Katowice, Institute of Physics, 75 Pułku Piechoty 1, 41-500 Chorzów, Poland
University of Silesia in Katowice, Silesian Centre of Education & Interdisciplinary Research, 75 Pułku Piechoty 1a, Chorzów 41-500, Poland

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

Article history: The search for new methods to remove the excess cholesterol molecules, precursors of plaque deposition in
Received 2 March 2018 an early phase of atherosclerosis disease, is a vital subject of molecular medicine and our studies are related
Received in revised form 17 April 2018 to this issue. The cyclodextrins have already been used in pharmaceutical industry mainly as complexing
Accepted 19 April 2018 agents to increase the aqueous solubility of poorly water-soluble drugs, and to increase their bioavailabil-
Available online 24 April 2018
ity and stability. The cavity diameter of b-cyclodextrin molecule has been found to be the most appropriate
size for hormones, vitamins, and other compounds frequently used in tissue and cell culture applications.
Keywords: Using the molecular dynamics simulation method we studied the system composed of b-cyclodextrin (bCD)
Cholesterol
molecules and cholesterol clusters, both standalone and in a water environment. We found that two con-
b-cyclodextrin
figurations of bCD–cholesterol complexes appear. The occurrence of the particular complex configuration is
Molecular dynamics
strongly related to the presence of water environment. We have found that bCD molecules do not penetrate
the interior of cholesterol cluster, rather stick or “glue” to these cholesterol molecules that make up the sur-
face of the cluster. Moreover, our simulations have shown that the ability of bCD to pull cholesterol molecule
out of the cluster surface is rather limited. Consequently, some chemical modifications of b-cyclodextrin
molecule should be considered while searching for the oligosaccharide based tools (nanomedicine) able
to effectively influence cholesterol deposit in the inner part of blood arteries.
© 2018 Elsevier B.V. All rights reserved.

1. Introduction gaps between phospholipids. Increased fluidity of the bilayer, on the

Cholesterol is a special type of lipid, known as a sterol due to its
molecular structure made of the steroid and alcohol. The molecular
structure of sterols consists of four connected hydrocarbon rings (bulk
part). Hydrophobic hydrocarbon group is linked to the bulk region
composed of four carbon rings. An alcohol component (OH group) is
located on the other side of a bulk region. Cholesterol is present in
all mammalian (including human) cell membranes (biomembranes)
with amounts varying from approximately 20% to about 50%. How-
ever, it is absent in the intracellular as well as prokaryote membranes.
The so far performed experimental and computational studies have
shown that cholesterol is one of the most important lipid molecules
in biomembranes, due to its functional ability to modulate their phys-
ical properties [1,2]. It is well-known, for instance, that the fluidity
of the cell membrane is regulated by cholesterol concentration. The
stiffening of the bilayer is a result of cholesterol appearance in the
* Corresponding author.
E-mail address: zygmunt.gburski@us.edu.pl (Z. Gburski).
other hand, is a consequence of the bending of hydrocarbon groups in
phospholipid molecules which takes place when cholesterol is present
at a very low concentration. Consequently, cholesterol is essential
for cell viability with the maintenance of the appropriate cell mem-
brane structure being its key function. Cholesterol also circulates with
the bloodstream as a component of lipoproteins and can be found in
the lymphatic fluid of the human body. There is a large amount of
literature on the role of cholesterol in biosystems [2-5].
Although cholesterol is essential for the functioning of cell mem-
branes, its excess may prove unhealthy. Atherosclerosis is an inflam-
matory disease linked to elevated blood cholesterol concentrations.
Atherosclerosis is the underlying pathology that causes heart attacks,
stroke, and peripheral vascular disease. Despite ongoing advances
in the prevention and treatment of atherosclerosis, cardiovascu-
lar disease remains the leading cause of death worldwide [6].
Atherosclerosis is characterized by arterial wall remodeling, which
is initiated by the retention and accumulation of different classes of
lipids in the subendothelial layer. Lipid deposition and the appear-
ance of cholesterol crystals have been associated with the induction
of an inflammatory reaction in the vessel wall, which contributes

https://doi.org/10.1016/j.molliq.2018.04.098
0167-7322/© 2018 Elsevier B.V. All rights reserved.
452 D. Makieła et al. / Journal of Molecular Liquids 262 (2018) 451–459

to the pathogenesis [7,8]. Hence, therapeutic strategies aimed at
the prevention of cholesterol phase transition or the removal of
cholesterol deposit could reduce tissue inflammation and disease
progression. Pharmacological reduction [9-11] of high-cholesterol
concentrations is among the most successful therapeutic approaches
to reduce the risk of developing cardiovascular disease and stroke,
but adequate reduction of low-density lipoprotein (LDL) cholesterol
is not possible in all patients. Many studies have shown that bCD
increases cholesterol water solubility in the body and thus pre-
vents and partially reverses atherosclerosis [12]. The search for new
methods to remove the excess cholesterol molecules, precursors of
plaque deposition in an early phase of atherosclerosis disease, is a
vital subject of molecular medicine and our simulations are related
to this issue. We have decided to study the impact of the cyclic
oligosaccharide b-cyclodextrin (bCD) on cholesterol clusters, both
standalone and in a water environment. Needless to say, taking
into account the level of the complexity of the system studied, only
the classical molecular dynamics (MD) technique can be effectively
applied, ab initio simulations would require an enormous amount of
computational resources.
conditions. The structures of cholesterol and bCD molecules (taken
from [16] and [17-19]) are shown in Fig. 1.
The temperature was maintained, employing Langevin thermo-
stat with a damping coefficient of 1 ps −1 . The cutoff distance for
all non-bonding interactions was set to 10 Å. The same systems but
in water environment were also simulated, in this case the periodic
boundary conditions were applied. The initial simulation box was
set to 100× 100× 100 Å. The number of water molecules packed in
this box was: 31 063, 30 693 and 29 568 for bCD:cholesterol ratios
1:1, 1:2 and 1:5, respectively. In these simulation runs pressure was
controlled using Langevin barostat. The reference pressure was set
to 1 atm. The Langevin piston was used to control the pressure at

2. Simulation details

The MD simulations were performed using the NAMD 2.11 [13]

with the all-atom CHARMM force field [14] and visualized with VMD
1.9.2 [15]. The first studied systems are clusters composed of 9 bCD
and n = 9, 18, 45 cholesterol molecules with no periodic boundary

Fig. 2. The equilibrium configuration of bCD and cholesterol for a) binary system and
Fig. 1. The structure of a) b-cyclodextrin and b) cholesterol molecules - VMD b) water system at T = 320 K. The water molecules are not shown for the clarity of the
visualization. picture.
 D. Makieła et al. / Journal of Molecular Liquids 262 (2018) 451–459 453

Fig. 3. The sequence of snapshots visualizing the process of transformation from the sandwich-like structure to cholesterol core surrounded by bCD molecules in water
environment, at T = 320 K. The water molecules are not shown for clarity.

1 atm, with a piston period of 100 fs, a damping time constant of 50 fs. NPT (constant number of particles, constant pressure, and constant
Long-range electrostatic forces were taken into account by means temperature) ensemble was performed over 1 • 107 time steps. The
of the Particle Mesh Ewald [20] approach. The equilibration in the integration time step was set to Dt = 1.0 fs for all simulation runs.
454 D. Makieła et al. / Journal of Molecular Liquids 262 (2018) 451–459

The standard NAMD integrator (Brünger–Brooks–Karplus algorithm)

was used [21]. Next, the “production” phases were started, the
duration was 20 ns for clusters and 50 ns for bulk samples with water.
During this stage the data were collected every 2000 simulation steps
(2 ps). The systems were simulated at six temperatures (T = 280,
290, 300, 310, 320, and 330 K). All interactions in the simulated sys-
tems were described with CHARMM potential. The CHARMM force
field includes intramolecular harmonic stretching Vbond , harmonic
bending Vangle , torsional Vdihedral terms:

Vtotal = Vbond + Vangle + Vdihedral + VvdW + VCoulomb . (1)

where

Vbond = Kr (r − r0 )2 (2)

Vangle = KH (H − H0 )2 . (3)


K0 (1 + cos(n0 − c)) n = 0.
Vdihedral = (4)
K0 (0 − c)2 n = 0.

 12  6 
s s
VvdW = 44 − . (5)
r r

Fig. 4. The radial distribution functions for in bCD:cholesterol ratio a) 1:1 and b) 1:5
at temperature range 280–330 K in water system.
The last two terms in equation for the total potential energy
Vtotal of the system, come from the nonbonding interactions: van der
Waals forces modeled with the standard Lenard-Jones 12–6 poten-
tial VvdW (with the Lorentz-Berthelot mixing rules) and electrostatic
interactions VCoulomb . Atomic charges on cholesterol molecule were

Fig. 5. The average number of hydrogen bonds per one bCD as a function of temperature for various bCD:cholesterol ratios. The hydrogen bonds are calculated between bCD and
water molecules.
 D. Makieła et al. / Journal of Molecular Liquids 262 (2018) 451–459 455

Fig. 6. The average number of hydrogen bonds per bCD as a function of temperature for various bCD:cholesterol ratios. The hydrogen bonds are calculated between bCD and
cholesterol molecules in anhydrous system.

taken from [17]. The TIP3P CHARMM model [22] was used in our
simulations. It should be noted, that the applied water model does
not correctly reproduce water translational diffusion, nevertheless
the entire CHARMM force field was fitted to describe interaction of
biological compounds with this particular model. All molecules used
in our studies were modeled on the full atomistic level.

3. Results and discussion

We have constructed the initial configuration by placing nine

bCD molecules between two layers of cholesterols (sandwich-like
structure), then MD simulations were performed. An example of
the obtained equilibrium configuration without water at T = 320 K
is shown in Fig. 2a. Apparently, the initially configured sandwich-
like structure essentially survived the equilibration and production
phases of simulations. Therefore, in the absence of water we do
not observe the mixing of bCD and cholesterol molecules. The equi-
librium configuration of the same system studied in water envi-
ronment is presented in Fig. 2b. Interestingly, in case with water
the equilibrium configuration is substantially, qualitatively different,
the cholesterol “core” surrounded by bCD molecules was formed.
It means that in water environment the attractive component of
cholesterol-cholesterol interaction prevails its counterpart in bCD-
cholesterol pair. As a result, the cholesterol molecules have the ten-
dency to “get together” forming the homogenous cholesterol cluster
(core), whereas b-cyclodextrin molecules stick to the cluster surface.
The interaction cholesterol-bCD is too weak to pull the cholesterol
molecules out of the core.
Therefore, the influence of water is quite significant for the
studied system. In the next figure (Fig. 3) we supply the sequence
of snapshots visualizing the process of transformation of the initial,
sandwich-like structure to the final one, i.e. cholesterol core sur-
rounded by bCD molecules. The radial distribution function g(r),
calculated between the hydrogen atom attached to the second order
OH group of bCD and oxygen atom in water (see Fig. 1a), is shown
in Fig. 4. We observe the development of three clearly marked
pikes (coordination spheres) with their maxima around 3.5, 5.5,
8.25 Å. The locations of g(r) maxima depend only very slightly on the
bCD:cholesterol ratio. The maxima are visibly sensitive to the vari-
ation of temperature. The lower the temperature, the highest and
sharper is each g(r) peak. This effect is rather typical for dense media.
It means that with raising of temperature, the coordination spheres Fig. 7. Type of complexes.
456 D. Makieła et al. / Journal of Molecular Liquids 262 (2018) 451–459

Fig. 8. Percentage quantity of bCD-cholesterol complexes as a function of time with

Fig. 10. Average percentage of type 1 complex as a function of temperature for var-
distinction of type of complexes. These are single sample runs which we obtained for
ious bCD: cholesterol ratios: a) anhydrous, b) aqueous system. On the vertical scale
anhydrous system (without aquatic environment) for bCD:cholesterol ratio 1:5 at T =
(0.0–30.0%) the plot in a) is practically flat, so we placed the insert with a thinner scale
320 K.
(0.0–0.1%).

Fig. 9. Percentage quantity of bCD-cholesterol complexes as a function of time with

distinction of type of complexes. These are single sample runs which we obtained for Fig. 11. Average percentage of type 2 complex as a function of temperature for
aquatic environment system, for bCD:cholesterol ratio 1:2 at T = 330 K. various bCD: cholesterol ratios: a) anhydrous, b) aqueous system.
 D. Makieła et al. / Journal of Molecular Liquids 262 (2018) 451–459
becoming a bit fuzzy, less defined – a consequence of gradual tran-
sition from well-defined structure at low temperature, to a softer
phase at higher temperature.
In Fig. 5 we show the calculated average number of hydro-
gen bonds per one bCD molecule as a function of temperature,
for several bCD:cholesterol ratios in water environment. Hydrogen
bonds are calculated between bCD and water molecules. A hydro-
gen bond is formed between an atom with a hydrogen bonded to
it (the donor, D) and another atom (the acceptor, A) provided that
the distance D-A is less than the cut-off distance (default 3.0 Å)
and the angle D-A-H is less than the cut-off angle (default 20◦ ),
see [15]. The plot in Fig. 5 indicates that the number of hydro-
gen bonds declines with the raising of temperature. Moreover, the
sensitivity of the number of hydrogen bonds to bCD:cholesterol
ratio is only marginal. In Fig. 6 we show the average number of
hydrogen bonds per one bCD molecule calculated between bCD
and cholesterol molecules in anhydrous system. Contrary to the
previous case, now the average number of hydrogen bonds substan-
tially depends on the bCD:cholesterol ratio and only weakly on the
variation of temperature. For low bCD:cholesterol ratios hydrogen
bonds between them appear sparsely.
In our computations two types of cholesterol-bCD complexes
were formed. These complexes are the ‘host-guest’ type inclusion
compounds in which cyclodextrin acts as a ‘host’ and partially
hydrophobic species are ‘guest’. The first complex was formed by
Fig. 12. RMSD as a function of temperature for various bCD:cholesterol ratios (anhy-
drous system) for a) bCD and b) cholesterol molecules.
457
the attraction of hydrophobic hydrocarbon group of the cholesterol
molecule with the hydrophobic interior of the bCD. This type of
structure is presented in Fig. 7a. The second complex is the result of
the interaction of four hydrocarbon rings (4 condensed hydrocarbon
rings) connected to the one OH group or oxygen bridges from bCD
interior (Fig. 7b). Both complexes are hydrophilic and water-soluble.
This makes it possible to transport cholesterol in the aquatic envi-
ronment. Both complexes are thermodynamically stable. However,
their binding energies are so low that the thermal motions cause
their lifetimes to be small and they undergo continual disintegration
and recreation. Depending on the actual, temporary configuration
of near neighbor molecules the first or second complex is preferred
and appears in large. There are more type 1 complexes (Fig. 7a)
in the aquatic environment, whereas type 2 complexes are pre-
ferred in anhydrous environment. The complex type 1 is preferred
in water surroundings; the hydrocarbon group of cholesterol enters
inside bCD whereas the carbon rings (with OH group attached) pro-
trude outside bCD. Although the cholesterol’s OH group is small,
comparing to the size of whole cholesterol, nevertheless it interacts
with surrounding water molecules creating energetically favorable,
temporary configuration. The structure of type 1 complex guaran-
tees the interaction of OH group with water molecules. Contrary,
in the absence of water surrounding the type 2 complex is pre-
ferred, where the hydrophobic group CH3 protrudes outside bCD
Fig. 13. RMSD as a function of temperature for various bCD:cholesterol ratios (aquatic
system) for a) bCD and b) cholesterol molecules.
458 D. Makieła et al. / Journal of Molecular Liquids 262 (2018) 451–459
molecule. In a series of subsequent figures we show the differ-
ences between the results for the system with and without water
environment.
In Figs. 8 and 9 we show the percentage of bCD-cholesterol
complexes (with reference to total number of bCD molecules) as a
function of time, with distinction of type of complexes for anhydrous
and aquatic system, respectively.
Figs. 10 and 11 again support our previous observation (Figs. 8, 9),
that in the absence of water the type 1 complexes practically do not
appear whereas they can form and are present in water environment.
We have also calculated the root mean square displacement of
atomic positions (RMSD) [23]. The calculations were performed sep-
arately for bCD and cholesterol molecules. In two subsequent figures,
the RMSD plots are presented, as a function of temperature for
various ratios bCD:cholesterol, in anhydrous (Fig. 12) and aquatic
(Fig. 13) system. The presented RMSD was determined as the average
of the course of the root mean square displacement with align-
ment i.e. the elimination of translator and rotatory displacement of
atoms [15], from the final part of the obtained trajectories (from
10 ns onward). Only the core atoms were taken into account (hydro-
gens were excluded from the calculations). The obtained results
show that the mobility of the cholesterols and bCD weakly depends
on temperature for aqueous and anhydrous systems. In the presence
of water the mobility of bCD is higher than cholesterol molecules,
Fig. 14. The radial distribution function between the oxygen atom of cholesterol and
oxygen atom from first order OH group of bCD for two bCD:cholesterol ratios: a) 1:1
and b) 1:5, at temperature range 280–330 K, for the system with no water.
while for the anhydrous system the situation is reversed. These
results can be explained by the structure of the formed clusters.
In water environment, bCD molecules form a shell surrounding the
cholesterol cluster (see Fig. 2b), while in the absence of water bCD
core is surrounded by the cholesterols (Fig. 2a), thus their mobility
is limited. The relatively low mobility of cholesterols and bCD in the
absence of water suggests, that the modeled clusters are in solid-like
phase. This conclusion is supported by the radial distribution func-
tion calculated between the oxygen atom of cholesterol and oxygen
atom from first order OH group of bCD in anhydrous system, pre-
sented in Fig. 14. The first, prominent peak of g(r) is located around
2.8 Å, so the oxygen atoms of bCD:cholesterol complex are close. This
feature is closely associated with the formation of type 2 complex.
The relatively weak temperature dependence of the shape of g(r)
curves suggests that the system is stable and exhibits amorphous
solid-like characteristic.
4. Conclusions
We performed a series of MD simulations of binary b-
cyclodextrin–cholesterol clusters in the presence and absence of
water. The influence of water is quite significant for the studied sys-
tem. In water environment the equilibrium configuration is formed
as the cholesterol “core” surrounded by bCD molecules. It means
that in water environment the attractive component of cholesterol-
cholesterol interaction prevails its counterpart in bCD-cholesterol
pair. As a result, the cholesterol molecules have the tendency to
“get together” forming the homogenous cholesterol cluster (core),
whereas b-cyclodextrin molecules stick to the cluster surface. We
found that two configurations of bCD–cholesterol complexes appear.
The occurrence of the particular complex configuration is strongly
related to the presence of water environment. Type 1 complex
(hydrocarbon cholesterol chain enters bCD inner cavity) is energet-
ically favored in water environment. Type 2 complex (cholesterol
bulk part and OH group enter bCD cavity) is preferred in anhy-
drous environment. Our simulations show that bCD is not directly
capable of solute the cholesterol cluster. The cholesterol–cholesterol
interactions prevail over the enhanced solubility of cholesterol–bCD
complexes. Therefore, the ability of bCD to pull cholesterol molecule
out of the cluster surface is rather limited. The results of our com-
puter experiments contribute to the considerations about future,
potential use of b-cyclodextrin in the context of combating with
atherosclerosis disease.
References
[1] E. Sackmann, Biological membranes architecture and function, Struct. Dyn.
Membr. 1 (1995) 1–63.
[2] T. Róg, M. Pasenkiewicz-Gierula, I. Vattulainen, M. Karttunen, Ordering
effects of cholesterol and its analogues, Biochim. Biophys. Acta Biomembr.
1788 (1) (2009) 97–121. lipid Interactions, Domain Formation, and Lat-
eral Structure of Membranes. http://www.sciencedirect.com/science/article/
pii/S0005273608002721. https://doi.org/10.1016/j.bbamem.2008.08.022.
[3] Z. Gburski, K. Górny, P. Raczyński, The impact of a carbon nanotube on the
cholesterol domain localized on a protein surface, Solid State Commun. 150
(9-10) (2010) 415–418.
[4] A. Finkelstein, A. Cass, Effect of cholesterol on the water permeability of thin
lipid membranes, Nature 216 (5116) (1967) 717.
[5] P. Raczyński, K. Gorny, M. Pabiszczak, Z. Gburski, Nanoindentation of
biomembrane by carbon nanotubes - MD simulation, Comput. Mater. Sci. 70
(2013) 13–18.
[6] J.D. Brunzell, M. Davidson, C.D. Furberg, R.B. Goldberg, B.V. Howard, J.H.
Stein, J.L. Witztum, Lipoprotein management in patients with cardiometabolic
risk, Diabetes Care 31 (4) (2008) 811–822.
[7] P. Duewell, H. Kono, K. Rayner, C. Sirois, G. Vladimer, F. Bauernfeind, G. Abela,
L. Franchi, G. Nũez, M. Schnurr, T. Espevik, E. Lien, K. Fitzgerald, K. Rock, K.
Moore, S. Wright, V. Hornung, E. Latz, NLRP3 inflammasomes are required for
atherogenesis and activated by cholesterol crystals, Nature 464 (7293) (2010)
1357–1361. https://doi.org/10.1038/nature08938.
 D. Makieła et al. / Journal of Molecular Liquids 262 (2018) 451–459
[8] F.J. Sheedy, A. Grebe, K.J. Rayner, P. Kalantari, B. Ramkhelawon, S.B.
Carpenter, C.E. Becker, H.N. Ediriweera, A.E. Mullick, D.T. Golenbock, et al.
CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular
nucleation of soluble ligands into particulate ligands in sterile inflammation,
Nat. Immunol. 14 (8) (2013) 812–820.
[9] T.E. Raptis, V.E. Raptis, J. Samios, New effective method for quantitative anal-
ysis of diffusion jumps, applied in molecular dynamics simulations of small
molecules dispersed in short chain systems, J. Phys. Chem. B 111 (49) (2007)
13683–13693.
[10] J.G. Robinson, M. Farnier, M. Krempf, J. Bergeron, G. Luc, M. Averna, E.S.
Stroes, G. Langslet, F.J. Raal, M. El Shahawy, et al. Efficacy and safety of
alirocumab in reducing lipids and cardiovascular events, N. Engl. J. Med. 372
(16) (2015) 1489–1499.
[11] P. Raczyński, K. Górny, J. Samios, Z. Gburski, Interaction between silicon-
carbide nanotube and cholesterol domain. A molecular dynamics simulation
study, J. Phys. Chem. C 118 (51) (2014) 30115–30119. https://doi.org/10.1021/
jp505532f.
[12] S. Zimmer, A. Grebe, S. Bakke, N. Bode, B. Halvorsen, T. Ulas, M. Skjelland,
D. De Nardo, L. Labzin, A. Kerksiek, C. Hempel, M. Heneka, V. Hawxhurst,
M. Fitzgerald, J. Trebicka, I. Bjorkhem, J.-A. Gustafsson, M. Westerterp, A.R.
Tall, E. Latz, Cyclodextrin promotes atherosclerosis regression via macrophage
reprogramming, 8 (2016)333ra50–333ra50.
[13] J.C. Phillips, R. Braun, W. Wang, J. Gumbart, E. Tajkhorshid, E. Villa, C. Chipot,
R.D. Skeel, L. Kalé, K. Schulten, Scalable molecular dynamics with NAMD, J.
Comput. Chem. 26 (16) (2005) 1781–1802. https://doi.org/10.1002/jcc.20289.
[14] B.R. Brooks, C.L. Brooks, A.D. Mackerell, L. Nilsson, R.J. Petrella, B. Roux,
Y. Won, G. Archontis, C. Bartels, S. Boresch, A. Caflisch, L. Caves, Q. Cui,
A.R. Dinner, M. Feig, S. Fischer, J. Gao, M. Hodoscek, W. Im, K. Kuczera, T.
Lazaridis, J. Ma, V. Ovchinnikov, E. Paci, R.W. Pastor, C.B. Post, J.Z. Pu, M.
Schaefer, B. Tidor, R.M. Venable, H.L. Woodcock, X. Wu, W. Yang, D.M. York,
M. Karplus, CHARMM: the biomolecular simulation program, J. Comput. Chem.
30 (10) (2009) 1545–1614. https://doi.org/10.1002/jcc.21287.
459
[15] W. Humphrey, A. Dalke, K. Schulten, VMD - Visual Molecular Dynamics, J. Mol.
Graph. 14 (1996) 33–38.
[16] E.P. Raman, O. Guvench, A.D. MacKerell, CHARMM additive all-atom force
field for glycosidic linkages in carbohydrates involving furanoses, J. Phys. Chem.
B 114 (40) (2010) 12981–12994. pMID: 20845956. https://doi.org/10.1021/
jp105758h.
[17] J. Hénin, C. Chipot, Hydrogen-bonding patterns of cholesterol in lipid mem-
branes, Chem. Phys. Lett. 425 (4) (2006) 329–335.
[18] J.B. Lim, B. Rogaski, J.B. Klauda, Update of the cholesterol force field param-
eters in CHARMM, J. Phys. Chem. B 116 (1) (2012) 203–210. pMID: 22136112.
https://doi.org/10.1021/jp207925m.
[19] M.C. Pitman, F. Suits, A.D. MacKerell, S.E. Feller, Molecular-level organization
of saturated and polyunsaturated fatty acids in a phosphatidylcholine bilayer
containing cholesterol, Biochemistry 43 (49) (2004) 15318–15328.
[20] T. Darden, D. York, L. Pedersen, Particle mesh Ewald: an N • log (N) method
for Ewald sums in large systems, J. Chem. Phys. 98 (12) (1993) 10089–10092.
[21] A. Brünger, C.L. Brooks, M. Karplus, Stochastic boundary condi-
tions for molecular dynamics simulations of ST2 water, Chem. Phys. Lett.
105 (5) (1984) 495–500. http://www.sciencedirect.com/science/article/pii/
0009261484800986. https://doi.org/10.1016/0009-2614(84)80098-6.
[22] W.L. Jorgensen, J. Chandrasekhar, J.D. Madura, R.W. Impey, M.L. Klein, Com-
parison of simple potential functions for simulating liquid water, J. Chem. Phys.
79 (2) (1983) 926–935. https://doi.org/10.1063/1.445869.
[23] E.A. Coutsias, C. Seok, K.A. Dill, Using quaternions to calculate RMSD, J.
Comput. Chem. 25 (15) (2004) 1849–1857.