Outer and inner leaflets of plasma cell membranes have different lipid compositions, and the membrane properties of each leaflet can differ from each other significantly due to these composition differences. However, because of the experimental difficulty in measuring the membrane properties for each leaflet separately, the differences are not well understood at a molecular level. In this study, we constructed two lipid bilayer systems, modeling outer and inner leaflets of plasma membranes of mouse hepatocytes based on experimental composition data. The ion concentration in the interlamellar water phase was also set to match the concentration in extra- and intracellular fluids. The differences in physical properties between the outer and inner leaflets of mouse hepatocyte cell membrane models were investigated by performing 1.2 μs-long all-atomistic molecular dynamics calculations under physiological temperature and pressure conditions (310.15 K and 1 atm). The calculated electron density profiles along the bilayer normal for each model bilayer system captured well the asymmetric feature of the experimental electron density profile across actual cell plasma membranes, indicating that our procedure of modeling the outer and inner leaflets of the cell plasma membranes was satisfactory. We found that compared to the outer leaflet model, the inner leaflet model had a very bulky and soft structure in the lateral direction. To confirm the differences, membrane fluidity was measured from the lateral diffusivity and relaxation times. The fluidity was significantly higher in the inner leaflet model than in the outer leaflet model. We also discuss two topics that are of wide interest in biology, i.e., the interdigitation of acyl tails of lipid molecules between two monolayers and the lateral concentration fluctuation of lipid molecules in the bilayers.
REFERENCES
1.
2.
The Structure of Biological Membranes
, 3rd ed., edited by P. L.
Yeagle
(CRC Press
, New York
, 2011
).3.
M.
Luckey
, Membrane Structural Biology: With Biological and Biophysical Foundations
, 2nd ed. (Cambridge University Press
, New York
, 2014
).4.
5.
Mammalian Cell Membranes
, edited by G. A.
Jamieson
and D. M.
Robinson
(Butterworths
, London
, 1976
), Vol. 1.6.
D. J.
Morre
, Annu. Rev. Plant Physiol.
26
, 441
(1975
).7.
W.
Dowhan
, Annu. Rev. Biochem.
66
, 199
(1997
).8.
M. S.
Bretscher
, Science
181
, 622
(1973
).9.
M. S.
Bretscher
, Nat. New Biol.
236
, 11
(1972
).10.
J. A. F.
Op den Kamp
, Annu. Rev. Biochem.
48
, 47
(1979
).11.
D. L. D.
Caspar
and D. A.
Kirschner
, Nat. New. Biol.
231
, 46
(1971
).12.
A.
Zachowski
and P. F.
Devaux
, Experienta
46
, 644
(1990
).13.
P. F.
Devaus
, Annu. Rev. Biophys. Biomol. Struct.
21
, 417
(1992
).14.
A.
Zachowski
, Biochem. J.
294
, 1
(1993
).15.
P. A.
Leventis
and S.
Grinstein
, Annu. Rev. Biophys.
39
, 407
(2010
).16.
K.
Simons
and E.
Ikonen
, Nature
387
, 569
(1997
).17.
S.
Munro
, Cell
115
, 377
(2003
).18.
L. J.
Pike
, Biochem. J.
378
, 281
(2004
).19.
D.
Lingwood
and K.
Simons
, Science
327
, 46
(2010
).20.
K.
Simons
and M. J.
Gerl
, Nat. Rev. Mol. Cell Biol.
11
, 688
(2010
).21.
E.
Sezgin
, I.
Levental
, S.
Mayor
, and C.
Eggeling
, Nat. Rev. Mol. Cell Biol.
18
, 361
(2017
).22.
J.
Israelachvili
, Intermolecular and Surface Forces
, 2nd ed. (Academic Press
, New York
, 1991
).23.
V.
Lladó
, D. J.
López
, M.
Ibarguren
, M.
Alonso
, J. B.
Soriano
, P. V.
Escribá
, and X.
Busquets
, Biochim. Biophys. Acta
1838
, 1619
(2014
).24.
C.
Bourgaux
and P.
Couvreur
, J. Controlled Release
190
, 127
(2014
).25.
S.
Pöyry
and I.
Vattulainen
, Biochim. Biophys. Acta
1858
, 2322
(2016
).26.
J. A.
Higgins
and W. H.
Evans
, Biochem. J.
174
, 563
(1978
).27.
P.
Emmelot
and R. P.
van Hoeven
, Chem. Phys. Lipids
14
, 236
(1975
).28.
R. P.
van Hoeven
and P.
Emmelot
, J. Membr. Biol.
9
, 105
(1972
).29.
R. P.
van Hoeven
, P.
Emmelot
, J. H.
Krol
, and E. P. M.
Oomen-Meulemans
, Biochim. Biophys. Acta
380
, 1
(1975
).30.
A.
Shevchenko
and K.
Simons
, Nat. Rev. Mol. Cell Biol.
11
, 593
(2010
).31.
M. R.
Wenk
, Cell
143
, 888
(2010
).32.
P. L.
Wood
, Alzheimer’s Res. Ther.
4
, 5
(2012
).33.
M.
Guéguinou
, A.
Gambade
, R.
Félix
, A.
Chantôme
, Y.
Fourbon
, P.
Bougnoux
, G.
Weber
, M.
Potier-Cartereau
, and C.
Vandier
, Biochim. Biophys. Acta
1848
, 2603
(2015
).34.
P. V.
Escribá
, X.
Busquets
, J.-i.
Inokuchi
, G.
Balogh
, Z.
Török
, I.
Horváth
, J. L.
Harwood
, and L.
Vígh
, Prog. Lipid Res.
59
, 38
(2015
).35.
P. V.
Escribá
, Biochim. Biophys. Acta
1859
, 1493
(2017
).36.
S.
Zalba
and T. L. M.
ten Hagen
, Cancer Treat. Rev.
52
, 48
(2017
).37.
D.
Santinha
, A.
Klopot
, I.
Marques
, E.
Ellis
, C.
Jorns
, H.
Johansson
, T.
Melo
, P.
Antonson
, T.
Jakobsson
, V.
Félix
, J.-Å.
Gustafsson
, M. R.
Domingues
, A.
Mode
, and L. A.
Helguero
, J. Steroid Biochem. Mol. Biol.
198
, 105558
(2020
).38.
R. M.
Venable
, Y.
Zhang
, B. J.
Hardy
, and R. W.
Pastor
, Science
262
, 223
–226
(1993
).39.
W.
Shinoda
, T.
Fukada
, S.
Okazaki
, and I.
Okada
, Chem. Phys. Lett.
232
, 308
–312
(1995
).40.
K.
Tu
, M. L.
Klein
, and D. J.
Tobias
, Biophys. J.
75
, 2147
–2156
(1998
).41.
A. M.
Smondyrev
and M. L.
Berkowitz
, Biophys. J.
77
, 2075
–2089
(1999
).42.
S. W.
Chiu
, E.
Jakobsson
, and H. L.
Scott
, Biophys. J.
80
, 1104
–1114
(2001
).43.
M. C.
Pitman
, F.
Suits
, A. D.
MacKerell
, Jr., and S. E.
Feller
, Biochemistry
43
, 15318
–15328
(2004
).44.
S. Y.
Bhide
, Z.
Zhang
, and M. L.
Berkowitz
, Biophys. J.
92
, 1284
–1295
(2007
).45.
Z.
Zhang
, S. Y.
Bhide
, and M. L.
Berkowitz
, J. Phys. Chem. B
111
, 12888
–12897
(2007
).46.
S. W.
Chiu
, S.
Vasudevan
, E.
Jakobsson
, R. J.
Mashl
, and H. L.
Scott
, Biophys. J.
85
, 3624
–3635
(2003
).47.
S. A.
Pandit
, S.
Vasudevan
, S. W.
Chiu
, R.
Jay Mashl
, E.
Jakobsson
, and H. L.
Scott
, Biophys. J.
87
, 1092
–1100
(2004
).48.
S. A.
Pandit
, E.
Jakobsson
, and H. L.
Scott
, Biophys. J.
87
, 3312
–3322
(2004
).49.
P. S.
Niemelä
, S.
Ollila
, M. T.
Hyvönen
, M.
Karttunen
, and I.
Vattulainen
, PLoS Comput. Biol.
3
, e34
(2007
).50.
R.
Vácha
, M. L.
Berkowitz
, and P.
Jungwirth
, Biophys. J.
96
, 4493
–4501
(2009
).51.
S.
Jo
, J. B.
Lim
, J. B.
Klauda
, and W.
Im
, Biophys. J.
97
, 50
–58
(2009
).52.
A.
Polley
, S.
Vemparala
, and M.
Rao
, J. Phys. Chem. B
116
, 13403
–13410
(2012
).53.
K. R.
Pandit
and J. B.
Klauda
, Biochim. Biophys. Acta
1818
, 1205
(2012
).54.
M.
Klähn
and M.
Zacharias
, Phys. Chem. Chem. Phys.
15
, 14427
–14441
(2013
).55.
Y.
Andoh
, S.
Okazaki
, and R.
Ueoka
, Biochim. Biophys. Acta - Biomembr.
1828
, 1259
(2013
).56.
Y.
Andoh
, N.
Aoki
, and S.
Okazaki
, J. Chem. Phys.
144
, 085104
(2016
).57.
A. V.
hughes
, D. S.
Patel
, G.
Widmalm
, J. B.
Klauda
, L. A.
Clifton
, and W.
Im
, Biophys. J.
116
, 1095
(2019
).58.
J. N.
Sachs
, P. S.
Crozier
, and T. B.
Woolf
, J. Chem. Phys.
121
, 10847
(2004
).59.
A. A.
Gurtovenko
, J. Chem. Phys.
122
, 244902
(2005
).60.
S.-J.
Lee
, Y.
Song
, and N. A.
Baker
, Biophys. J.
94
, 3565
(2008
).61.
A. A.
Gurtovenko
and I.
Vattulainen
, J. Phys. Chem. B
112
, 4629
(2008
).62.
B.
Alberts
, A.
Johnson
, J.
Lewis
, D.
Morgan
, M.
Raff
, K.
Roberts
, and P.
Walter
, Molecular Biology of the Cell
, 6th ed. (Garland Science
, New York
, 2014
).63.
J. B.
Klauda
, R. M.
Venable
, J. A.
Freites
, J. W.
O’Connor
, D. J.
Tobias
, C.
Mondragon-Ramirez
, I.
Vorobyov
, A. D.
MacKerell
, Jr., and R. W.
Pastor
, J. Phys. Chem. B
114
, 7830
(2010
).64.
R. M.
Venable
, A. J.
Sodt
, B.
Rogaski
, H.
Rui
, E.
Hatcher
, A. D.
MacKerell
, Jr., R. W.
Pastor
, and J. B.
Klauda
, Biophys. J.
107
, 134
(2014
).65.
J. B.
Lim
, B.
Rogaski
, and J. B.
Klauda
, J. Phys. Chem. B
116
, 203
(2012
).66.
S. R.
Durell
, B. R.
Brooks
, and A.
Ben-Naim
, J. Phys. Chem.
98
, 2198
–2202
(1994
).67.
T.
Darden
, D.
York
, and L.
Pedersen
, J. Chem. Phys.
98
, 10089
–10092
(1993
).68.
U.
Essmann
, L.
Perera
, M. L.
Berkowitz
, T.
Darden
, H.
Lee
, and L. G.
Pedersen
, J. Chem. Phys.
103
, 8577
–8593
(1995
).69.
M.
Parrinello
and A.
Rahman
, Phys. Rev. Lett.
45
, 1196
–1199
(1980
).70.
S.
Nosé
, Mol. Phys.
52
, 255
–268
(1984
).71.
W. G.
Hoover
, Phys. Rev. A
31
, 1695
–1697
(1985
).72.
G. J.
Martyna
, M. L.
Klein
, and M.
Tuckerman
, J. Chem. Phys.
97
, 2635
–2643
(1992
).73.
M.
Tuckerman
, B. J.
Berne
, and G. J.
Martyna
, J. Chem. Phys.
97
, 1990
–2001
(1992
).74.
G. J.
Martyna
, M. E.
Tuckerman
, D. J.
Tobias
, and M. L.
Klein
, Mol. Phys.
87
, 1117
–1157
(1996
).75.
Y.
Andoh
, N.
Yoshii
, A.
Yamada
, and S.
Okazaki
, J. Comput. Chem.
38
, 704
–713
(2017
).76.
Y.
Andoh
, N.
Yoshii
, K.
Fujimoto
, K.
Mizutani
, H.
Kojima
, A.
Yamada
, S.
Okazaki
, K.
Kawaguchi
, H.
Nagao
, K.
Iwahashi
, F.
Mizutani
, K.
Minami
, S.-i.
Ichikawa
, H.
Komatsu
, S.
Ishizuki
, Y.
Takeda
, and M.
Fukushima
, J. Chem. Theory Comput.
9
, 3201
(2013
).77.
W.
Humphrey
, A.
Dalke
, and K.
Schulten
, J. Mol. Graphics
14
, 33
(1996
).78.
W.
Shinoda
, N.
Namiki
, and S.
Okazaki
, J. Chem. Phys.
106
, 5731
(1997
).79.
J. B.
Klauda
, B. R.
Brooks
, and R. W.
Pastor
, J. Chem. Phys.
125
, 144710
(2006
).80.
M.
Roark
and S. E.
Feller
, J. Phys. Chem. B
113
, 13229
(2009
).81.
A.
Filippov
, G.
Orädd
, and G.
Lindblom
, Biophys. J.
84
, 3079
(2003
).82.
H. A.
Scheidt
, D.
Huster
, and K.
Gawrisch
, Biophys. J.
89
, 2504
(2005
).83.
G.
Lindblom
, G.
Orädd
, and A.
Filippov
, Chem. Phys. Lipids
141
, 179
(2006
).84.
Y.
Andoh
, S.
Kitou
, and S.
Okazaki
, J. Mol. Liquids
271
, 933
(2018
).85.
C.
Das
, M. G.
Noro
, and P. D.
Olmsted
, Biophys. J.
97
, 1941
–1951
(2009
).86.
T.
Róg
, A.
Orłowski
, A.
Llorente
, T.
Skotland
, T.
Sylvänne
, D.
Kauhanen
, K.
Ekroos
, K.
Sandvig
, and I.
Vattulainen
, Biochim. Biophys. Acta
1858
, 281
(2016
).87.
S.
Capponi
, J. A.
Freites
, D. J.
Tobias
, and S. H.
White
, Biochim. Biophys. Acta-Biomembr.
1858
, 354
–362
(2016
).88.
S.
Chianitia
and E.
London
, Biophys. J.
103
, 2311
(2012
).89.
J. P.
Hansen
and I. R.
MacDonald
, Theory of Simple Liquids: With Applications to Soft Matter
(Academic Press
, 2013
).90.
K.
Kinosita
, Jr., S.
Kawato
, and A.
Ikegami
, Biophys. J.
20
, 289
(1977
).91.
S.
Kawato
, K.
Kinosita
, Jr., and A.
Ikegami
, Biochemistry
16
, 2319
(1977
).92.
G.
Lipari
and A.
Szabo
, Biophys. J.
30
, 489
(1980
).93.
P. B.
Moore
, C. F.
Lopez
, and M. L.
Klein
, Biophys. J.
81
, 2484
(2001
).94.
R. W.
Pastor
and R. M.
Venable
, Acc. Chem. Res.
35
, 438
(2002
).95.
W.
Shinoda
, M.
Mikami
, T.
Baba
, and M.
Hato
, Chem. Phys. Lett.
390
, 35
(2004
).96.
J. B.
Klauda
, M. F.
Roberts
, A. G.
Redfield
, B. R.
Brooks
, and R. W.
Pastor
, Biophys. J.
94
, 3074
(2008
).97.
X.
Zhuang
, E. M.
Dávila-Contreras
, A. H.
Beaven
, W.
Im
, and J. B.
Klauda
, Biochim. Biophys. Acta
1858
, 3093
(2016
).98.
Y.
Andoh
, S.
Hayakawa
,and S.
Okazaki
, “Molecular dynamics study of lipid bilayers modeling outer and inner leaflets of plasma membranes of mouse hepatocytes. II: Lateral organization of lipid molecules and its correlation between two leaflets
,” (unpublished).© 2020 Author(s).
2020
Author(s)
You do not currently have access to this content.
