Activity Report 2022 / Supercomputer Center, Institute for Solid State Physics, The University of Tokyo

Molecular Dynamics Study of Ultra-Long Chain
Fatty Acid in Lipid Bilayer
Kazutomo KAWAGUCHI1 , and Hiroshi NOGUCHI2
1
Institute of Science and Engineering, Kanazawa University
Kanazawa, Ishikawa 920-1192
2
Institute for Solid State Physics, University of Tokyo
Kashiwa-no-ha, Kashiwa, Chiba 277-8581

Abstract
Although ultra-long-chain fatty acids (ULCFAs) exist in biomembranes in certain typesof tissues, their biological roles remain unknown. In this report, we review our recent
study on the molecular conformation of ULCFAs in lipid bilayers using molecular dynamics simulations. Their long chains exhibit characteristic fluctuations between elongated, Lshaped, and turned conformations. The ratiosof these conformations are changed in responseto the lipid-density differences between upperand lower leaflets. This response is faster than
the flip–flop of cholesterols.

1

Introduction

Biological membranes consist of various typesof lipids and proteins [1]. Phospholipids are
the most abundant lipids in biological membranes and have a polar head group and twohydrocarbon tails (fatty acids). Phospholipids
are biosynthesized by a combination of a polar head group and two hydrocarbon tails andhave a range of structural and functional roles
in biological cells [2, 3]. Each tail typically contains between 14 and 22 carbon atoms. Fatty
acids containing more than 22 carbons arecalled very-long-chain fatty acids (VLCFAs).
Moreover, much longer chains containing morethan 32 carbons were found at the sn-1 posi-tion of phosphatidylcholine (PC) in photoreceptors, fibroblasts, and keratinocytes [4, 5, 6].
These fatty acids are called ultra-long-chain
fatty acids (ULCFAs). It is considered that
ULCFAs are stored as a precursor of bioactive
lipid mediators [7] and derivatives of C32:6 andC34:6 are neuroprotective in retina [8]. However, the physicochemical properties of ULCFAs with respect to their structures and thebiological roles of ULCFA-containing phospholipids are still unclear.
Molecular simulations have been widely applied to study lipid membranes [9, 10, 11, 12,13]. All-atom molecular dynamics (MD) simulations for VLCFAs, in which the tail length of
the sn-1 chain is maximally 24, have also been
performed by a few groups [14, 15, 16, 17, 18].
It has been shown that the long hydrocarbon
chain is slightly interdigitated into the opposite
leaflet [14, 16, 17]. However, ULCFAs had notbeen simulated yet. To examine the effects ofultra-long chains, we have conducted all-atom
MD simulations for ULCFAs [19, 20]. Our
study revealed that the longer chains of ULCFAs have more strongly interacted with the
opposite leaflet than those of VLCFAs. The
ultra-long sn-1 chain of ULCFAs takes elongated, L-shaped, and turned conformations inlipid bilayers and that these conformationalchange can reduce the lipid-density difference
between upper and lower leaflets.
Three types of ULCFAs are used in this35

Activity Report 2022 / Supercomputer Center, Institute for Solid State Physics, The University of Tokyo

study. The chain length and number of unsaturated bonds are varied. Lipid molecules
composing Host bilayer membranes consist of
single or two types of phospholipids. Moreover,cholesterols (CHOLs) are embedded in the bilayer membrane to examine the effect of the
flip–flop of cholesterols.

2

Methods

2.1

ULCFAsThe molecular structures of ULCFAs used inthis study are shown in Fig. 1. Dotriacontahexaenoic acid containing phosphatidylcholine(dTSPC, C32:6-C18:0), which has an ultralong chain of 32 carbons with six double bonds
at the sn-1 position [Fig. 1(a)]. Hexacosatetraenoic acid containing phosphatidylcholine(HSPC, C26:4-C18:0), which has a very-longchain of 26 carbons with four double bonds atthe sn-1 position [Fig. 1(b)]. Lacceroic acidcontaining phosphatidylcholine (LSPC, C32:0C18:0), which has an ultra-long chain of 32
carbons with no double bonds at the sn-1 position [Fig. 1(c)]. All of the ULCFAs havea stearoyl chain at the sn-2 position. HSPC
is constructed by truncating the long hydrocarbon chain of dTSPC at C26, and LSPC isconstructed by the saturation of the long hydrocarbon chain of dTSPC. A single ULCFA
molecule (dTSPC, HSPC, or LSPC) was inserted into the lipid bilayers described in thenext section.

2.2

Lipid Bilayer

The molecular structures of lipids composing bilayer membranes are shown in Fig.
2. Distearoyl phosphatidylcholine (DSPC,
C18:0-C18:0) contains two saturated stearoyl
chains.
Stearoyl-DHA phosphatidylcholine(SDPC, C18:0-C22:6) contains a steroyl chain
and a docosahexaenoyl chain with six double
bonds at the sn-1 and sn-2 positions, respectively.
Stearoyl-oleoyl phosphatidylcholine

Figure 1: Molecular structures of ULCFAs.
(a) dTSPC (C32:6-C18:0), (b) HSPC (C26:4C18:0), and (c) LSPC (C32:0-C18:0).

(SOPC, C18:0-C18:1) contains a steroyl chain
and an oleoyl chain with a double bond at thesn-1 and sn-2 positions, respectively.

Figure 2: Molecular structures of lipids composing bilayer membranes. (a) DSPC (C18:0C18:0), (b) SDPC (C18:0-C22:6), and (c)SOPC (C18:0-C18:1).
We considered three types of host lipid
bilayers for embedding a single ULCFA
molecule: (1) single-component bilayers. (2)asymmetric-component bilayers, in which eachleaflet is composed of a single type of phospholipids. (3) two-component bilayers composedof a single type of phospholipids and cholesterols.

36

Activity Report 2022 / Supercomputer Center, Institute for Solid State Physics, The University of Tokyo(1) DSPC, SDPC, and SOPC were used
for single-component host bilayers and dTSPC
was used as ULCFA. A membrane bilayer consisting of 100 lipid molecules per leaflet was
prepared for each membrane system. The
membrane was connected by its periodic images in the xy plane under the periodic boundary conditions. A single lipid molecule in theupper leaflet was replaced by a single dTSPC
molecule for each single-component bilayer, inorder to examine the influence of the difference
between upper and lower leaflets on the longsn-1 chain of dTSPC (see Table 1). Ten lipid
molecules in the upper (lower) leaflet were removed in the ’189u’ (’189l’) system. Four lipid
molecules in the upper (lower) leaflet were removed in the ’195u’ (’195l’) system. Two lipid
molecules in the upper (lower) leaflet were removed in the ’197u’ (’197l’) system. Labels
189, 195, and 197 represent the total numberof the host lipid molecules. The number ofwater molecules per lipid was fixed at 50 in allcases. The lipids do not flip–flop to the opposite leaflets on a simulation time scale (the flip–
flop time is typically hours or days [21]). The
difference of the lipid numbers between the twoleaflets results in the deviation of the lipid density from a stable value even under zero surface
tension, as described by an area-differenceelasticity model [22, 23]. Thus, the lipids inthe leaflet with higher density are more compressed, although a flat membrane connectedby the periodic boundary does not bend because of the symmetry. The DSPC/dTSPC
and SDPC/dTSPC mixtures were equilibrated
for 200 ns, which was followed by 800-ns production runs at 343 K. to avoid the gel phaseof DSPC and SDPC. The SOPC/dTSPC mixtures were equilibrated for 400 ns, which was
followed by 1.6 µs-production runs at 303 K.
(2) A DSPC/SDPC mixture asymmetric bilayer was used as a host lipid bilayer. We
prepared six types of host lipid bilayers withdifferent numbers of lipids, as shown in Table 2. A single ULCFA molecule was inserted

Table 1: Numbers of phospholipids in singlecomponent host bilayers. A single dTSPC
molecule was embedded.
Model
Upper leaflet Lower leaflet
DS189u89 DSPCs
100 DSPCs
DS189l99 DSPCs
90 DSPCs
DS197u97 DSPCs
100 DSPCs
DS197l99 DSPCs
98 DSPCs
SD189u89 SDPCs
100 SDPCs
SD189l
99 SDPCs
90 SDPCs
SD197u97 SDPCs
100 SDPCs
SD197l
99 SDPCs
98 SDPCs
SO189u89 SOPCs
100 SOPCs
SO189l99 SOPCs
90 SOPCs
SO195u95 SOPCs
100 SOPCs
SO195l99 SOPCs
96 SOPCs
SO197u97 SOPCs
100 SOPCs
SO197l99 SOPCs
98 SOPCs

Table 2:
Numbers of phospholipids inasymmetric-component host bilayer membranes. Three types of ULCFAs were embedded in the bilayers.
MembraneUpper leaflet Lower leaflet
DS89-SD100 89 DSPCs
100 SDPCs
DS99-SD90
99 DSPCs
90 SDPCs
DS99-SD98
99 DSPCs
98 SDPCs
SD89-DS100 89 SDPCs
100 DSPCs
SD99-DS90
99 SDPCs
90 DSPCs
SD99-DS98
99 SDPCs
98 DSPCs

into the upper leaflet. The system temperature was controlled at 343 K to avoid the gelphase of DSPC and SDPC. The membranes
were equilibrated for 200 ns, followed by 800
ns production runs.
(3) We added cholesterols to both the upperand lower leaflets of the bilayer to investigate
the effects of cholesterols on the conformationof the ULCFAs. DSPC and SDPC were usedas the host lipid molecules. The number ofhost lipid molecules is 89 in the upper leaflet,and 100 in the lower leaflet. In the initial state,
20 or 40 cholesterols are added in both upper37

Activity Report 2022 / Supercomputer Center, Institute for Solid State Physics, The University of Tokyo

Table 3: Numbers of lipids in bilayers containing cholesterols. A single dTSPC molecule wasembedded.
MembraneUpper leaflet Lower leaflet
DS/CHOL20 89 + 20
100 + 20
DS/CHOL40 89 + 40
100 + 40
SD/CHOL20 89 + 20
100 + 20
SD/CHOL40 89 + 40
100 + 40
and lower leaflets, as listed in Table 3. The
system temperature was controlled at 343 K
to avoid the gel phase of DSPC and SDPC.
The DS/CHOL and SD/CHOL mixtures were
equilibrated for 1 µs and 3 µs, respectively.

2.3

MD Simulations

The system pressure of all simulations was controlled at 0.101 MPa. The CHARMM 36 force
field [24] and TIP3P water model [25] wereused to represent lipid and water molecules, respectively. All MD simulations were performed
using GROMACS [26].
To calculate the lipid area in the tensionless membranes, we performed MD simulations
for a pure symmetric membrane consisting of
100 DSPCs or 100 SDPCs per leaflet. Fromthese MD simulations, we obtained that thearea per lipid of DSPC and SDPC are 0.63
and 0.74 nm2 , respectively. Thus, SDPCs havea slightly larger area than DSPCs because of
their unsaturated bonds.

3

Results and Discussion

3.1

Conformation of the sn-1 chainof ULCFAs

Figure 3 shows three types of conformations of
the sn-1 chain of dTSPC embedded in SD189u
bilayer. A turned conformation, in which the
C3 -C18 -C32 angle in the sn-1 chain is approximately 0◦ is shown in Fig. 3(a). The terminal carbon atom (C32 ) is located in the upper
leaflet. An L-shaped conformation, in which
the angle is approximately 90◦ , is shown in Fig.

3(b). The C32 atom is located at the boundaryof the two leaflets. An elongated conformation,in which the angle is approximately 180◦ , isshown in Fig. 3(c). The C32 is located in thelower leaflet. The sn-1 chain temporally fluctuates among these conformations. That is,
it moves between the upper and lower leaflets
and also lies along with the interface between
the two leaflets. This conformational fluctuation is rapid, and the transit time between two
leaflets is ∼ 10 ns. This large conformational
fluctuation has not been observed in the otherlipids and is specific to ULCFAs. In particular,
the elongated conformation penetrates deeply
into the opposite leaflet.
These three types of conformations were also
observed for dTSPC, HSPC, and LSPC embedded in asymmetric membranes (case 2) under all simulated conditions. Three types ofconformations of dTSPC, HSPC, and LSPC
are shown in Fig. 4(a), (b), and (c), respectively. The long chain of LSPC is more elongated than that of dTSPC owing to the saturated bonds of the chain.

3.2

Distribution of atoms

The distribution of atoms in the sn-1 chain of
ULCFA in a lipid bilayer was calculated along
the z-axis, which is parallel to the bilayer normal. The origin of the z-axis is set at the centerof the lipid bilayer. Figure 5 shows the probability distribution of C3 , C18 , and C32 atomsof the sn-1 chain of dTSPC and phosphate (P)atoms of DSPC, SDPC, and SOPC in singlecomponent bilayers (case 1). The terminal carbon C32 of the sn-1 chain is widely distributed
from z of −2 to 2 nm, corresponding withthe conformation fluctuations observed in thesnapshots. The free-energy difference F (z) between two conformations were calculated using
F (z) = −kB T ln(p(z)). The estimated value
was less than 1.2kB T from p(z) of C32 , indicating no apparent free-energy barrier amongthem.
The distributions of P in DS189u, SD189u,38

Activity Report 2022 / Supercomputer Center, Institute for Solid State Physics, The University of Tokyo

Figure 3: Snapshots of dTSPC in DS189l
membrane. (a) Turned conformation. (b) Lshaped conformation. (c) Elongated conformation. dTSPC are represented by coloredspheres. Host lipid molecules are shown in gray(spheres represent the phosphate atoms). Water molecules are not shown for clarity.

and SO198u were similar to those in DS189l,
SD189l, and SO198l, respectively. as shown in
Fig. 5. These results indicate that the membrane thickness does not depend on the lipiddensity difference between the two leaflets.
Thus, the host lipid bilayer structure is not
significantly modified in the examined rangeof the density difference.
In contrast, the distribution of carbon atoms
in the sn-1 chain of dTSPC depends on
the lipid-density difference between the twoleaflets. As the lipid density relatively de-

Figure 4: Snapshots of (a) dTSPC, (b) HSPC,
and (c) LSPC embedded in lipid bilayers(DS89-SD100). Carbon atoms in the sn-1
chain are shown in cyan and other carbon
atoms are shown in gray. Hydrogen atoms
are not shown for clarity. Reproduced from
Ref. [20].

creases in the lower leaflet, the distributionof C32 largely shifts toward the lower leaflet.
The peak position of C18 shifts toward thelower leaflet as observed in C32 , but the shiftmagnitude is smaller. The distribution of C3
shifts slightly toward the lower leaflet as thelipid density relatively decreases in the lower
leaflet. Thus, the longer region (C18 ∼ C32 ) of
the sn-1 chain exhibits larger changes arisingfrom the lipid-density difference between the
two leaflets.
To quantitatively investigate the effects of
the lipid-density differences on the conformation of the sn-1 chain, we calculated the mean
z-position of the C atoms normalized by themean z-position the P atoms as a function of
the lipid density ratio. The lipid density ratio

39

Activity Report 2022 / Supercomputer Center, Institute for Solid State Physics, The University of Tokyo
(a)
0.20

dTSPC-sn1-C3
dTSPC-sn1-C18
dTSPC-sn1-C32
DSPC-P

p(z)

0.15
0.10

0.05

0.00
(b)
0.20

-3

-2

-1

0
z / nm

1

2

3

-1

0
z / nm

1

2

3

-1

0
z / nm1

2

3

dTSPC-sn1-C3
dTSPC-sn1-C18
dTSPC-sn1-C32
SDPC-P

p(z)

0.15
0.10

0.05

0.00
(c)
0.20

-3

-2

dTSPC-sn1-C3
dTSPC-sn1-C18
dTSPC-sn1-C32
SOPC-P

p(z)

0.15
0.10

0.05

0.00

-3

-2

the normalized z-positions of carbon atoms
and the lipid density ratio.
From the least-squares fitting (represented
by dashed lines), we found that the value ofzC /zP was almost 0 for C32 at Nl Sl /Nu Su = 1.
Thus, the terminal carbon is located in the
middle of the lipid bilayer in the absence oflipid-density difference and moves to the upper (lower) leaflet as the lipid density of theupper (lower) leaflet decreases. Therefore, theconformational change of the sn-1 chain in dTSPC reduces the lipid-density differences.
In the cases of HSPC and LSPC, we foundsimilar behavior. The ratio of the elongatedconformation increases as the lipid density ofthe opposite leaflet decreases. The position theterminal atom C26 of HSPC is almost identical to that of C26 in dTSPC. The sn-1 chain of
LSPC is more deeply in the lower leaflet thanthat of dTSPC. We concluded that the reduction of the lipid-density differences between the
two leaflets by the change in the ultra-long sn1 chain conformation is a general property of
ULCFAs.

3.3
Figure 5: Probability distribution of atoms in(a) DS189u/l, (b) SD189u/l, and (c) SO189u/l
systems. The solid and dotted lines represent
the probability distributions in ’u’ and ’l’, respectively. Reproduced from Ref. [19].

is defined as Nl Sl /Nu Su , where Nl and Nu are
the numbers of host lipid molecules in the lower
and upper leaflets, respectively. Sl and Su represent the area per lipid of DSPC or SDPCin the lower and upper leaflets, respectively,
obtained from the MD simulations for a puresymmetric membrane.
Figure 6 shows the correlation between thenormalized z-position (zC /zP ) and the lipid
density ratio Nl Sl /Nu Su for dTSPC in the
DSPC/SDPC asymmetric bilayer (case 2). A
positive linear correlation was found between

Order parameters

We calculated the lipid order parameters, SCD ,using the following equation:
SCD = ⟨

3 cos2 α − 1
⟩,
2

(1)

where α is the angle between C-H bond vector and the bilayer normal. The brackets indicate the average over time and lipid molecules.
Calculated order parameter profiles, −SCD , for
ULCFAs embedded in the DS89-SD100 bilayer
are shown in Fig. 7. These profiles were notsensitive to lipid-density differences. The order profiles of the sn-1 chain decreased to 0
at C15 and exhibited a low order in the longer
region until the terminal. The order of the sn2 chain was similar to that of the sn-2 chain
in DSPC, because the sn-2 chain in ULCFAs
are equivalent to the sn-2 chain in DSPC. In
the case of HSPC, the order profile of the sn-1

40

Activity Report 2022 / Supercomputer Center, Institute for Solid State Physics, The University of Tokyo(a) DSPC (upper) / SDPC (lower)
DS99-SD90
DS99-SD98
0.3

(a)
0.3

DS89-SD100

0.2

0.2
-SCD

zC / zP

0.1
0.0
-0.1

C18
C26
C32
y = 0.44 x -0.34
y = 0.56 x -0.53
y = 0.54 x -0.53

-0.2
-0.3
1.0

dTSPC sn-1
dTSPC sn-2

1.1

1.2
NlSl / NuSu

1.3

0.1

0.0
0

5

10

(b)

1.4

15 20
Carbon0.3(b) SDPC (upper) / DSPC (lower)
SD99-DS90 SD99-DS98
SD89-DS100
0.3

25

30

35

30

35

30

35

HSPC sn-1
HSPC sn-2

-SCD

0.2

0.2

0.1

zC / zP

0.1
0.0

0.0

0

-0.1

C18
C26
C32
y = 0.52 x -0.39
y = 0.83 x -0.78
y = 0.86 x -0.85

-0.2
0.8

0.9
NlSl / NuSu

1.0

1.1

15 20
Carbonchain exhibited a similar profile to that in dTSPC, because the sn-1 chain in HSPC is equivalent to the sn-1 chain until C26 in dTSPC. In
contrast, the order profile of LSPC becomes
higher toward the terminal, because the sn-1
chain of the LSPC has no double bonds. It is
indicated that the saturated long chain takes
a more elongated conformation than unsaturated long chains.

dTSPC with Cholesterols

We analyzed the interactions between dTSPC and cholesterols in asymmetric bilayers.
Cholesterol molecules were embedded in theasymmetric bilayers with number fractions of
20 % or 40 %, as shown in Table 3. In theinitial state of each simulation, the cholesterol

25

LSPC sn-1
LSPC sn-2

0.2

Figure 6: Correlation between normalized zposition of C atoms and lipid-density ratio for
dTSPC. Reproduced from Ref. [20].

3.4

10

0.3

-SCD

-0.3
0.7

5

(c)

0.1

0.0
0

5

10

15 20
Carbon25

Figure 7: Order parameter profiles, −SCD ,of (a) dTSPC, (b) HSPC, and (c) LSPC for
DS89-SD100. Reproduced from Ref. [20].

fraction in the upper leaflet (Nupper /Ntotal ) was
set to 0.5.
In the case of the DSPC bilayers, the cholesterol fraction is almost constant (0.5) during 1µs, showing that the flip–flop time of cholesterols is much longer than 1 µs. On the other
hand, in the case of the SDPC bilayers, thefraction frequently changed during 3 µs, showing that the lipid-density difference between
the two leaflets was reduced by cholesterols.
The flip–flop times per cholesterol molecule
were 0.52 and 0.66 µs for SD/CHOL20 and41

Activity Report 2022 / Supercomputer Center, Institute for Solid State Physics, The University of Tokyo

SD/CHOL40, respectively. These values offlip–flop time are much faster than those ofphospholipids (hours or days) but slower thanthose of ULCFAs. A similar time scale of thecholesterol flip–flop was previously reported in
the MD simulations of other lipid compositions[27, 28, 29]. After the cholesterol flip–flop, theconformation distribution of ULCFAs becomesclose to that in the absence of the area difference in the two leaflets. Therefore, the area
difference is responded by ULCFAs first andlater by cholesterols. ULCFAs is a rapid sensor of the area difference.

4

Summary

In this report, we have shown the conformational change of ULCFAs in single-component
and asymmetric bilayer membranes using MD
simulations. The ultra-long sn-1 chain largely
fluctuates between upper and lower leaflets andtakes elongated, L-shaped, and turned conformations. ULCFAs can rapidly reduce the lipiddensity differences between the two leaflets via
the ratio change of these conformations.

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