Download Water behaviors at lipid bilayers/water interface

Water behaviors at lipid bilayers/water interface under various force fields
LI WeiXin1,2, WU Yuan-Yan2, TANG GuoNing1*, TU YuSong2*
1
College of Physics and Technology, Guangxi Normal University, Guilin 541004, China
2
College of Physics Science and Technology, Yangzhou University, Jiangsu 225009, China
Abstract:
Water properties at lipid bilayer/water interfaces are of essential importance for the dynamics, stability and
function of biological membrane, strongly associated to numerous biological processes at the interfaces of
lipid bilayers. Most of force fields, including the united-atom Berger force fields and its recent improved
versions, and all-atom Slipid force field developed recently in 2011, can be applied to simulate the structures
of lipid bilayer, in good agreement with the results from experiments. However, in the work, we find there
are evident differences between the behaviors of water at lipid bilayer/water interfaces when various force
fields are considered in molecular dynamics simulations, with the focus on the hydrogen-bonding structure
and its energy profiles at water/lipid bilayer interfaces. These results would be helpful in understanding the
behaviors of water at the lipid bilayer/water interfaces and provide a guide for making the appropriate choice
on various force filed in simulations of lipid bilayers.
1.
Introduction
As Lipid bilayers are self-assembled structures in water environments, and numerous biological
processes at the interfaces of lipid bilayers and their relevant biological functions strongly depends on
microscopic properties of water on this interfaces of phospholipid bilayers. Biomembrane is an essential
component of cell, and the structure and function of biomembrane are closely related to the properties of
water at the interface of biomembrane. The properties of biomembrane strongly influence the water
molecules at the biomembrane interface [1], as well as strongly depend on them [2]. For example, the results
from neutron scattering on the interactions between hydration water and biological membrane have shown
that the self-diffusion coefficient for the first layer of water at the membrane interface is five times smaller
than that of bulk water [3]. In fact, phospholipid bilayers are often functioned as model biological membrane
and an increasing number of experimental studies on the interaction of hydration water and phospholipid
bilayers have been reported [4]. Using 2H-NMR technology, Arnold et al have shown that there are still
about five tightly bound water molecules per phospholipid molecule in phosphatidylcholine(PC), though
several bound water molecules are extracted from phospholipids system by poly(ethylene glycol) [5]. By
high-pressure infrared spectroscopic method, Wong et al have provide an evidence of water of binding sites
in phospholipids, indicating that no hydrogen bonds between water and the ester C=O group of the sn-1 acyl
chain of PC [6]. Combined IR spectroscopy and quantum-chemical calculation, Pohle et al conclude that
hydrogen-bonding can occur between water and apolar methyl and methylene groups in lipid headgroup [7].
Recently, a sum frequency generation spectroscopy study by Mondal et al indicated that the water molecules
at the membrane interface have heterogeneous orientations in response to local charged groups [8].
With the development of computer technology, molecular dynamics simulations have been a powerful
tool for our understanding the water behaviors at the water/lipid bilayers membrane interface at the atomic
or near-atomic level and have provide detailed molecular description of many biological phenomena [9, 10].
So far, a large number of results on investigations of interactions between lipid membrane and water using
molecular dynamics simulations have been gained [11-15] ： Pasenkiewicz-Gierula et al have employed
simulations of a hydrated lipid bilayers composed of dimyristoylphosphatidylcholine (DMPC) to study the
H-bond network forming at the membrane interface, and found that different DMPC oxygens or oxygens
coming from different DMPC molecules can simultaneously H-bond to the same water--"water bridge",
forming H-bond network [11]. Róg et al have investigated the influence of lipid bilayers on dynamics of
water at the lipid bilayers surface, and found that the dynamics properties of water decrease with the
distance from the bilayers surface [12]. Lopez et al have reported that hydrogen bonding structure and
dynamics of the water molecules at the bilayers surface and found the average number of hydrogen bonds
per oxygen in phospholipid varies with the location of water molecules near a lipid headgroup and the
deeply buried oxygens have a longer H-bond lifetime [13]. Berkowitz's group have systematically study the
structural and dynamical properties of water at the lipid bilayers interface and shown significant differences
in the properties of water in different regions of phospholipids bilayers [14]. More recently, Re et al [15]
have observed a mosaic of water orientation structures on the surface of a neutral phosholipid bilayers which
has been reported by Mondal [8].
In fact, in order to perform theoretical simulations of lipid bilayers in a better way, many efforts have
been paid to develop more accurate force fields for the simulations of lipid bilayers to obtain better fitting
resutls with experimental data. Thus, a number of parameter sets have been proposed such as the
united-atom force fields including a widely used version of the Berger parameters (here called Berger
parameters) [16], the modification suggested by Kukol [17] (called Kukol parameters) and the parameters
set based on Gromos-53A6 and Berger parameters by Poger [18] (called Poger parameters) , and the
all-atom force fields such as CHRAMM36 parameters [19] and Slipid parameters [20], as well as Lipid 14
parameters [21]. Most of these parameters sets can reproduce the structural properties of lipid bilayers such
as bilayers thicknesses, the area per lipid, deuterium order parameters for the hydrophobic acyl chains of
lipids and average electron density profiles of lipid bilayers, with comparable accuracy of the available
experimental data. However, through detailed analyse of properties of structure and behaviors of water at the
lipid bilayers interface under different force fields, we find that behaviors of water at bilayers interface
display clear differences. In this paper, we present a detailed comparison of behaviors of water at a fully
hydrated bilayers interface based on the DPPC model using three united-atom force fields, namely Berger
parameters, Kukol parameters, Poger parameters, and one all-atom force field, namely Slipid parameters.
Although many structural properties of the lipid bilayers from the four force fields are in good agreement
with experimental results, the hydrogen bond energy distributions of hydrogen bonds between water
molecules at the membrane interface and lipid molecules and the hydrogen bond network display significant
differences such as the peak energies of the hydrogen bond energy distribution of double bonded oxygen in
phosphate group and the average number of these oxygens. we hope our results can contribute to a better
understanding of these water molecules behaviors and choosing a more appropriate force filed in
biomembrane simulations.
2
2.1
Systems and Methods
Systems
We performed molecular dynamics simulations on systems including water molecules and a membrane
composed by 128 dipalmitoylphosphatidylcholines (DPPC), to investigate difference of hydrogen bond
properties of interfacial water and study the water behaviors at the bilayers membrane interface using four
force fields. The DPPC molecule (see Figure 2A) consists of the glycerol backbone linked to the
phosphatidylcholine moiety and attached to two acyl tails. DPPC includes eight oxygens (carboxylic
oxygens O33, O34, O22, O12, and ether oxygens O31, O32, O21, O11), which are highlighted in Figure 2A.
Here we call (change to “named” or “defined”?) O22 and O21 along with their attached carbon atoms as
C=O2 group, O11 and O12 along with their attached carbon atoms as C=O1 group. As mentioned above, we
perform four simulations using four parameters, namely Kukol , Poger parameters, Berger parameters, and
Slipid parameters. Berger parameters consist of standard Gromos87 parameters [22] and OPLS parameters
[23], with some modifications by the authors. The Kukol parameters were developed from Berger
parameters and Gromos 53A6 parameters [24] with some modifications to carbonyl carbons which increase
accuracy of membrane protein simulations. Poger parameters also were developed from Berger and base on
Gromos 53A6 parameters. Unlike Kukol parameters, Poger used new atom types for the methyl groups of
the choline headgroup and ester oxygens in the phosphate group. Derived from CHARMM 36, the all-atom
Slipid parameters recalculate the parameters of lipid tails by using even more precise an initio methods in an
Amber force field consistent manner.
2.2
Molecular dynamics simulation
All molecular dynamics simulations were performed using the Gromacs 4.5 program [25]. The initial
membrane system contained 128 DPPC molecules and about 6000 water molecules. The leap frog algorithm
[26] was applied for the integration and LINCS algorithm [27] was used for all bonds for the systems, which
allow a time step of 2 fs (Is this logic ture? I have no idea about MD but sure you have.). Periodic boundary
conditions were applied in all three dimensions and the box size fluctuated around values of 6.30 * 6.33 *
8.73 nm3. Four systems were maintained at a temperature of 323 K using the Berendsen coupling algorithm
[28] to lipids and water separately, with a coupling constant of 0.1 ps. The systems were coupled to a
Berendsen barostat [28] with a barostat time constant of 2.0 ps, and a reference pressure of 1 atm in the
lateral and normal direction separately. The electrostatic interactions were calculated using the particle mesh
Ewald method [29], with a real space cutoff of 1.2 nm, grid spacing of 0.12 nm, and a fourth-order spline
interpretation. The Lennard-Jones interactions were truncated at 1.2 nm.
The simple point charge model of water [30] was employed in all simulation systems except for the
Slipid simulation, in which TIP3P water model [31] was chosen to be the water modelbecause TIP3P is the
default water model for Slipid parameters. Each system was run for 70 ns, in which the coordinates and
velocities were saved every 1 ps. The first 20 ns were discarded for equilibration and the last 50 ns
trajectories were used for analysis.
We employed a geometric definition of the H-bond between water and DPPC molecules [32, 33]. A
water molecule was assumed to form a hydrogen bond to the oxygen in DPPC when the distance between
the oxygen of water molecule and oxygen of DPPC was less than 3.5 nm, and the angle θ between one of
OH bonds of the water molecule and the vector linking the DPPC and water oxygens is less than 30°. The
hydrogen bond energy E [33] was defined as the sum of electrostatic energy between water and
corresponding lipid group to which the oxygens are affiliated,
, where qi is the charge of
atom i of the water molecule and the q j is the charge of atom j of group in DPPC. rij is the distance
between atom i of water and atom j of DPPC . f is a constant of 138.93 kJ mol-1 nm e-2.
3
3.1
Result and discussion
Structure properties of the lipid bilayers
Firstly, we analyzed several important structural properties of lipid bilayers including area per lipid, the
average density profiles for various components of the DPPC bilayers and the deuterium order parameters of
DPPC. The results are in good agreement with the original papers [references]. In our simulations, the
values of area per lipid gained from four systems are in the range of 0.62-0.63nm2. As shown in Figure 1, we
present the average density profiles for water and different groups of the DPPC from the bilayers center
from one united-atom force field (Berger) and one all-atom force field (Slipid), and the deuterium order
parameters of hydrocarbon chains for DPPC, whose definition can be found from Ref. 18 [18]. The results
indicate that no matter these simulations using either the used united-atom or all-atom force fields, the
structural properties of lipid bilayers gained from our simulations are within the experimental range and can
well describe lipid bilayers basic structure properties.
Figure 1
The average density profiles for water and different groups of the DPPC as a function of distance
from the bilayers center (z) and the deuterium order parameters of hydrocarbon chains for DPPC. A: density
profiles of simulated system using Berger parameters, and C: density profiles of simulated system using
Slipid parameters. B: the deuterium order parameters of DPPC using Berger parameters and D: the
deuterium order parameters of DPPC using Slipid parameters.
3.2 The hydrogen bond energy distribution of different oxygens in lipid from Berger parameters
We have carefully analyzed interfacial water behaviors with four different force fields, which are found
to be greatly different from each other. At the interface of phoshpolipid bilayers, water molecules are mostly
hydrogen bonded to the eight oxygens of DPPC: O31, O32, O33, O34, O21, O22, O11, O12, as shown in
Figure 2A.
The interactions between water and lipid strongly affect their H-bonding. In order to investigate these
influences comprehensively, we calculate the H-bonds energy distributions between water and lipid, as
shown in Figure 2. Firstly, the energies of H-bonds formed between waters in the vicinity of DPPC and
oxygens in DPPC were calculated the distribution based on statistical analysis from three H-bonds energy
classifications as follow: 1) H-bond energy of every oxygen in DPPC, 2) the energy of H-bond between a
water molecule and one group in DPPC, 3) the sum energies of all H-bonds formed in one group of a DPPC
molecule.
Figure 2
A, Illustration of a DPPC lipid molecule, with atom names and group names referenced
throughout the text indicated. B, The H-bond energy distribution of every oxygen in DPPC. C, The H-bond
energy distributions between a water molecule and one group in DPPC, where the numbers nearby the
curves are the average H-bond energy. D, The distribution of sum of H-bond energy for one group in DPPC.
Figure 2 presents the H-bonds energy distributions from Berger force filed using three H-bonds energy
classifications as mentioned above. As shown in Figure 2B, different oxygens have different distributions of
H-bonds energy and the double bonded oxygens in the same group have a slightly wider distribution
compared to the single bonded oxygens in the same group. For exemple, H-bonds energy distributions of the
O33 and O34 in phosphate group are wider compared to the O31 and O32 in phosphate group, and C=O1
and C=O2 group are the same as phosphate group. The H-bond energy distributions of three groups in DPPC
are presented in Figure 2C , from which it can be seen that average H-bond energy of phosphate group and
absolute value of average H-bond energy are the largest in three groups, indicating that H-bonds interactions
between water and phosphate group are stronger. Figure 2D shows the sum energies distributions of all
H-bonds formed in one group and it exhibits several peaks in phosphate group and C=O2, meaning several
stable energy configurations. Furthermore, we can observe that the peak energies are integer multiples of the
average energy of corresponding group, such as the four obvious peak energies of phosphate group are about
-50, -110, -160, -220 kJ mol-1, which are one or two, three, and four times of the average energy of
phosphate group (-50.2 kJ mol-1), the same as C=O2. Therefore, we can conclude that the phosphate group
mostly forms three or four H-bonds, the probability of other H-bond numbers is small. So the distributions
of sum energies of H-bonds formed in one group in the DPPC also indicate the distributions of H-bonds
numbers formed in one group of the DPPC molecule.
3.3 The hydrogen bond energy distribution of different oxygens in lipid using different parameters.
In this section we will compare hydrogen bond energy distribution of different oxygens in lipid bilayers
at the water/lipid interface from four lipid parameters sets to find the difference of H-bonds network
between water and lipid, and study the interfacial water behaviors under different force fields. As the above
analysis of Berger parameters, Figure 3 and Figure 4 present the distributions of hydrogen bond energy
between water and lipid from different parameters. Additionally, we also calculate the average number of
H-bonds of different oxygens from four parameters, as shown in Table 1.
The distribution curves and their peak energies of the H-bond energies of eight oxygens from Kukol
parameters are similar to that from Poger parameters, as shown in Figure 3 A and B. However, as the same
united-atom force fields, the Berger parameters display some difference compared to the two former
parameters. Compared to united-atom force fields, the hydrogen bond energy distribution from the
simulation with Slipid parameters display the greatest differences. Although the H-bond energies
distributions of O33 and O34 from four parameters are completely overlap (see Figure 3A, B and C), which
are essentially the same for both, their peak energies from different parameters are different, in which the
peak energies from Slipid parameters are the highest, flowed by Berger, Kukol and Poger. And the average
numbers of H-bonds of O33 are close to that of O34, as shown in table 1. Completely overlap of H-bond
energies distributions of O33 and O34 reflects the symmetry of phosphate group, which was previously
reported by Lopez [13]. Due to the difference of the peak energies of O33 and O34 from different
parameters, the H-bond numbers of the both oxygens from Slipid parameters are nearly lager one times than
that of united-atom force fields. But for the remaining oxygens in DPPC, their H-bond distributions from
Slipid parameters are closer to original point and the average numbers of the remaining oxygens are small
compared to O33 and O34, but the contributions of H-bonds numbers from the O22 and O32 are not
negligible with united-atom force fields.
Table 1 The average numbers of H-bonds for different oxygens under different force fields.
Force Field
Oxygen
O31
O32 O33
O34
O21
O22
O11 O12
Sum
Kukol
0.14
0.37
0.87
0.90
0.05
1.34
0.29
0.53
4.49
Poger
0.13
0.37
0.97
0.90
0.07
1.03
0.03
0.32
3.82
Berger
0.13
0.41
1.47
1.50
0.18
1.44
0.07
0.49
5.69
Slipid
0.13
0.04
1.96
1.96
0.03
0.75
0.01
0.80
5.68
Figure 3
The probability of hydrogen bond energy distribution of eight individual lipid oxygens with
different parameters. A,with Kukol parameters; B, with Poger parameters; C, with Berger parameters; D,
with Slipid parameters. Refer to Figure 2A for the oxygen labels.
Figure 4
The distribution of sum H-bond energy (Is that right with this phrase?) of different lipid groups
in DPPC from different parameters. A, for Kukol; B, for Poger; C, for Berger; D, for Slipid. Refer to Figure
2A for the group labels.
To compare the differences of sum H-bond energy of lipid groups from different parameters, we plot
the distribution of sum H-bond energy of different lipid groups in DPPC under four force fields, as shown in
Figure 4. The distributions of hydrogen bond energy of phosphate group with four parameters show several
peaks, and Kukol and Poger parameters have three peaks, however the Berger parameters have 4 peaks, with
a wider distribution. For all-atom force field, Slipid parameters also have four obvious peak, with a shoulder
at -285 kJ mol-1, indicating the evidence of a fifth peak. For the C=O2 group, they have two peaks with
united-atom parameters, however, the Slipid parameters have only one peak. As discussed previously in
previous section, the sum energies distributions of all H-bonds formed in one group in the DPPC molecule
also indicate the distributions of H-bonds numbers formed in one group in the DPPC molecule. It can be
seen that with the Kukol and Poger parameters the probability forming one, two, or three H-bonds in
phosphate group show little difference, while the fourth peak for Slipid has higher probability, meaning
generally forming four H-bonds in phosphate group. As shown in Table 1, on average, both O33 and O34
from Slipid parameters have about 2 H-bonds, which make the phosphate group having 4 H-bond in a high
probability. Having one peak in distributions of C=O2 group with all-atom parameters indicates one H-bond
formed, which is a another great difference compared to three united-atom force fields.
From Table 1, it can be seen that the H-bonds between water and DPPC are mostly formed in the double
bonded oxygens in the three groups, namely O33, O34, O22, O12. The proportion of H-bonds in the four
oxygens from Kukol is 81%, from Poger is 84%, from Berger is 86%, and from Slipid is 96%. But, the
numbers of H-bond in O22 from four different parameters are different, the H-bonds of O22 are larger than
that of O33 and O34. However, Slipid parameters are not the case and numbers of H-bonds of O22 are
smaller one time than that of O33 and O34, which explaine
only one peak in C=O2 group in Figure 4.
Finally, how do the distributions of sum of hydrogen bond energy in different lipid groups from different
parameters affect the properties of the H-bonds network at the water/lipid interface? As shown in table 1, the
H-bonds between water and DPPC with four parameters are 4.49, 3.82, 5.69, 5.68, respectively, and the
results from Berger and Slipid parameters are close to the data ( 5.3 H-bonds ) reported by
Pasenkiewicz-Gierula [11] and are in agreement with probability of hydrogen bonds by Lopez [13].
Although one water may be simultaneously h-bonded to two different oxygens forming intermolecular
bridges, in which the proportion is small, so the average H-bonds numbers formed in DPPC from Berger and
Slipid parameters are in good with the five bound water molecules from Arnold's experiment.
4
Conclusions
In this paper, we investigated the behaviors of water at lipid bilayer/water interfaces under three
united-atom force fields (Beger, Kukol and Poger) and an all-atom force field (Slipid) in MD simulations.
We find all these force fields can be applied to simulate the structures of lipid bilayer, in good agreement
with the results from experiments, including the area per lipid, the mass distributions of different groups
positions, and the deuterium order parameters of hydrocarbon chains in the structures of lipid bilayers
(DPPC). However, there are evident differences between the water behaviors at lipid bilayer/water interfaces
for the four force fields of lipid bilayers. At lipid bilayer/water interfaces, the formation of hydrogen bonds
between water molecules and phospholipids are mostly involved with the eight oxygen atoms of hydrophilic
heads of DPPC, and more than 80% of these hydrogen bonds are linked to the four double-bonded oxygen
atoms in the eight oxygen atoms, namely O33, O34, O22, O12. We compare the results of these hydrogen
bonds for the four force fields, and find the proportion of the hydrogen bonds linked to the four double
bonded oxygens in all hydrogen bonds of phosholipids with water for the all-atom force field (Slipid) is up
to 96% and is much larger than those for three used united-atom force fileds, and the averaged numbers of
hydrogen bonds for the four double bonded oxygens are evidently different. Further, we compare the energy
distribution of hydrogen bonds between the eight oxygen atoms of hydrophilic heads and water and also
between different head groups of phospholipids and water for the four force fields. Obviously, in comparison
with the Slipid force field, the three used united-atom force fileds evidently weaken hydrogen bonds of the
phosphate groups of phospholipids with water, but in contrast those hydrogen bonds of the glycerol groups
are enlarged. The implicit treatment of all aliphatic hydrogen atoms of phospholipids can reduce the
great computation cost with respect to all-atom lipid force field, but the difference of water
behaviors we observe between different lipid force fields would bring about evident influence on
various interacting processes at lipid bilayers/water interfaces, e.g., membrane-protein interactions.
The realistic hydrogen-bonding structures at lipid bilayers/water interfaces remain unknown due to
the lack of experimental data, but these differences should be noticed in relevant studies of lipid
bilayers, especially when involving to water behaviors in the vicinity of the surface of lipid bilayers.
Our present results contribute to a delicate understanding of water molecule behaviors at lipid bilayer/water
interfaces.
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