Pentameric ligand-gated ion channels (pLGICs), embedded in the lipid membranes of nerve cells, mediate fast synaptic transmission and are major pharmaceutical targets. Because of their complexity and the limited knowledge of their structure, their working mechanisms have still to be fully unraveled at the molecular level. Over the past few years, evidence that the lipid membrane may modulate the function of membrane proteins, including pLGICs, has emerged. Here, we investigate, by means of molecular dynamics simulations, the behavior of the lipid membrane at the interface with the 5-HT3A receptor (5-HT3AR), a representative pLGIC which is the target of nausea-suppressant drugs, in a nonconductive state. Three lipid compositions are studied, spanning different concentrations of the phospholipids, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine, and of cholesterol, hence a range of viscosities. A variety of lipid interactions and persistent binding events to different parts of the receptor are revealed in the investigated models, providing snapshots of the dynamical environment at the membrane-receptor interface. Some of these events result in lipid intercalation within the transmembrane domain, and others reach out to protein key sections for signal transmission and receptor activation, such as the Cys-loop and the M2-M3 loop. In particular, phospholipids, with their long hydrophobic tails, play an important role in these interactions, potentially providing a bridge between these two structures. A higher cholesterol content appears to promote lipid persistent binding to the receptor.

1.
D.
Lemoine
,
R.
Jiang
,
A.
Taly
,
T.
Chataigneau
,
A.
Specht
, and
T.
Grutter
,
Chem. Rev.
112
,
6285
(
2012
).
2.
Á.
Nemecz
,
M. S.
Prevost
,
A.
Menny
, and
P.-J.
Corringer
,
Neuron
90
,
452
(
2016
).
3.
R. J. C.
Hilf
and
R.
Dutzler
,
Nature
457
,
115
(
2009
).
4.
N.
Bocquet
,
H.
Nury
,
M.
Baaden
,
C.
Le Poupon
,
J.-P.
Changeux
,
M.
Delarue
, and
P.-J.
Corringer
,
Nature
457
,
111
(
2009
).
5.
L.
Sauguet
, et al.,
Proc. Natl. Acad. Sci. U.S.A.
111
,
966
(
2014
).
6.
P. S.
Miller
and
A. R.
Aricescu
,
Nature
512
,
270
(
2014
).
7.
T.
Althoff
,
R. E.
Hibbs
,
S.
Banerjee
, and
E.
Gouaux
,
Nature
512
,
333
(
2014
).
8.
G.
Hassaine
, et al.,
Nature
512
,
276
(
2014
).
9.
X.
Huang
,
H.
Chen
,
K.
Michelsen
,
S.
Schneider
, and
P. L.
Shaffer
,
Nature
526
,
277
(
2015
).
10.
J.
Du
,
W.
,
S.
Wu
,
Y.
Cheng
, and
E.
Gouaux
,
Nature
526
,
224
(
2015
).
11.
M.
Kudryashev
,
D.
Castaño-Díez
,
C.
Deluz
,
G.
Hassaine
,
L.
Grasso
,
A.
Graf-Meyer
,
H.
Vogel
, and
H.
Stahlberg
,
Structure
24
,
165
(
2016
).
12.
M.
Nys
, et al.,
Proc. Natl. Acad. Sci. U.S.A.
113
,
E6696
(
2016
).
13.
S.
Zhu
,
C. M.
Noviello
,
J.
Teng
,
R. M.
Walsh
,
J. J.
Kim
, and
R. E.
Hibbs
,
Nature
559
,
67
(
2018
).
14.
15.
S.
Basak
,
Y.
Gicheru
,
S.
Rao
,
M. S. P.
Sansom
, and
S.
Chakrapani
,
Nature
563
,
270
(
2018
).
16.
17.
V.
Corradi
,
B. I.
Sejdiu
,
H.
Mesa-Galloso
,
H.
Abdizadeh
,
S. Y.
Noskov
,
S. J.
Marrink
, and
D. P.
Tieleman
,
Chem. Rev.
119
,
5775
(
2019
).
18.
M. J.
Thompson
and
J. E.
Baenziger
,
Biochim. Biophys. Acta
1862
,
183304
(
2020
).
19.
C. J.
Baier
,
J.
Fantini
, and
F. J.
Barrantes
,
Sci. Rep.
1
,
69
(
2011
).
21.
G.
Brannigan
,
J.
Hénin
,
R.
Law
,
R.
Eckenhoff
, and
M. L.
Klein
,
Proc. Natl. Acad. Sci. U.S.A.
105
,
14418
(
2008
).
22.
J. E.
Baenziger
,
J. A.
Domville
, and
J. D.
Therien
, in Sterol Regulation of Ion Channels, edited by I. Levitan (Academic, New York, 2017), Vol. 80, pp. 95–137.
24.
C. J. B.
daCosta
and
J. E.
Baenziger
,
J. Biol. Chem.
284
,
17819
(
2009
).
25.
C. J. B.
daCosta
,
L.
Dey
,
J. P. D.
Therien
, and
J. E.
Baenziger
,
Nat. Chem. Biol.
9
,
701
(
2013
).
26.
N. B.
Guros
,
A.
Balijepalli
, and
J. B.
Klauda
,
Proc. Natl. Acad. Sci. U.S.A.
117
,
405
(
2020
).
27.
J.
Hénin
,
R.
Salari
,
S.
Murlidaran
, and
G.
Brannigan
,
Biophys. J.
106
,
1938
(
2014
).
28.
M. A.
Dämgen
and
P. C.
Biggin
,
Structure
28
,
130
139.E2
(
2020
).
29.
P.
Kumar
,
Y.
Wang
,
Z.
Zhang
,
Z.
Zhao
,
G. D.
Cymes
,
E.
Tajkhorshid
, and
C.
Grosman
,
Proc. Natl. Acad. Sci. U.S.A.
117
,
1788
(
2020
).
30.
A.
Tong
,
J. T. n.
Petroff
,
F.-F.
Hsu
,
P. A.
Schmidpeter
,
C. M.
Nimigean
,
L.
Sharp
,
G.
Brannigan
, and
W. W.
Cheng
,
eLife
8
,
e50766
(
2019
).
31.
C. M.
Hénault
, et al.,
Nat. Chem. Biol.
15
,
1156
(
2019
).
32.
S.
Basak
,
N.
Schmandt
,
Y.
Gicheru
, and
S.
Chakrapani
,
eLife
6
,
e23886
(
2017
).
33.
S. A.
Heusser
,
M.
Lycksell
,
X.
Wang
,
S. E.
McComas
,
R. J.
Howard
, and
E.
Lindahl
,
Proc. Natl. Acad. Sci. U.S.A.
115
,
10672
(
2018
).
34.
S. M.
Patra
,
S.
Chakraborty
,
G.
Shahane
,
X.
Prasanna
,
D.
Sengupta
,
P. K.
Maiti
, and
A.
Chattopadhyay
,
Mol. Membr. Biol.
32
,
127
(
2015
).
35.
M. I.
Mahmood
,
X.
Liu
,
S.
Neya
, and
T.
Hoshino
,
Chem. Pharm. Bull.
61
,
426
(
2013
).
36.
M.
Jafurulla
,
B. D.
Rao
,
S.
Sreedevi
,
J.-M.
Ruysschaert
,
D. F.
Covey
, and
A.
Chattopadhyay
,
Biochim. Biophys. Acta
1838
,
158
(
2014
).
37.
R.
Dawaliby
,
C.
Trubbia
,
C.
Delporte
,
M.
Masureel
,
P.
Van Antwerpen
,
B. K.
Kobilka
, and
C.
Govaerts
,
Nat. Chem. Biol.
12
,
35
(
2016
).
38.
D. E.
Elmore
and
D. A.
Dougherty
,
Biophys. J.
85
,
1512
(
2003
).
39.
L.
Dominguez
,
L.
Foster
,
J. E.
Straub
, and
D.
Thirumalai
,
Proc. Natl. Acad. Sci. U.S.A.
113
,
E5281
(
2016
).
40.
P. V.
Escribá
,
A.
Ozaita
,
C.
Ribas
,
A.
Miralles
,
E.
Fodor
,
T.
Farkas
, and
J. A.
García-Sevilla
,
Proc. Natl. Acad. Sci. U.S.A.
94
,
11375
(
1997
).
41.
H. I.
Ingólfsson
, et al.,
J. Am. Chem. Soc.
136
,
14554
(
2014
).
42.
S. J.
Marrink
,
V.
Corradi
,
P. C.
Souza
,
H. I.
Ingólfsson
,
D. P.
Tieleman
, and
M. S.
Sansom
,
Chem. Rev.
119
,
6184
(
2019
).
43.
R.
Cao
,
G.
Rossetti
,
A.
Bauer
, and
P.
CarIoni
,
PLoS ONE
10
,
e0126833
(
2015
).
44.
V.
Oakes
and
C.
Domene
,
J. Mol. Biol.
431
,
1633
(
2019
).
45.
R. B.
Chan
,
T. G.
Oliveira
,
E. P.
Cortes
,
L. S.
Honig
,
K. E.
Duff
,
S. A.
Small
,
M. R.
Wenk
,
G.
Shui
, and
G.
Di Paolo
,
J. Biol. Chem.
287
,
2678
(
2012
).
46.
F. W.
Pfrieger
,
Biochim. Biophys. Acta
1610
,
271
(
2003
).
47.
A.
Filippov
,
G.
Orädd
, and
G.
Lindblom
,
Biophys. J.
84
,
3079
(
2003
).
48.
H.
Li
and
V.
Papadopoulos
,
Endocrinology
139
,
4991
(
1998
).
49.
J.
Fantini
and
F. J.
Barrantes
,
Front. Physiol.
4
,
31
(
2013
).
50.
J.
Fantini
,
C.
Di Scala
,
L. S.
Evans
,
P. T. F.
Williamson
, and
F. J.
Barrantes
,
Sci. Rep.
6
,
21907
(
2016
).
51.
D.
Di Maio
,
B.
Chandramouli
, and
G.
Brancato
,
PLoS ONE
10
,
1
(
2015
).
52.
S.
Yuan
,
S.
Filipek
, and
H.
Vogel
,
Structure
24
,
816
(
2016
).
53.
M. Y.
Antonov
,
A. V.
Popinako
, and
G. A.
Prokopiev
,
AIP Conf. Proc.
1773
,
060001
(
2016
).
54.
A.
Crnjar
,
F.
Comitani
,
W.
Hester
, and
C.
Molteni
,
J. Phys. Chem. Lett.
10
,
694
(
2019
).
55.
C. X.
Weichenberger
and
M. J.
Sippl
,
Nucleic Acids Res.
35
,
W403
W406
(
2007
).
56.
S.
Jo
,
T.
Kim
,
V. G.
Iyer
, and
W.
Im
,
J. Comput. Chem.
29
,
1859
(
2008
).
57.
J.
Shan
,
G.
Khelashvili
,
S.
Mondal
,
E. L.
Mehler
, and
H.
Weinstein
,
PLoS Comput. Biol.
8
,
e1002473
(
2012
).
58.
J. C.
Phillips
, et al.,
J. Comput. Chem.
26
,
1781
(
2005
).
59.
J. A.
Maier
,
C.
Martinez
,
K.
Kasavajhala
,
L.
Wickstrom
,
K. E.
Hauser
, and
C.
Simmerling
,
J. Chem. Theory Comput.
11
,
3696
(
2015
).
60.
C. J.
Dickson
,
B. D.
Madej
,
Å.. A.
Skjevik
,
R. M.
Betz
,
K.
Teigen
,
I. R.
Gould
, and
R. C.
Walker
,
J. Chem. Theory Comput.
10
,
865
(
2014
).
61.
D. J.
Smith
,
J. B.
Klauda
, and
A. J.
Sodt
,
Living J. Comp. Mol. Sci.
1
,
5966
(
2018
).
62.
C.
Kandt
,
W. L.
Ash
, and
D. P.
Tieleman
,
Methods
41
,
475
(
2007
).
63.
W. V.
Kraske
and
D. B.
Mountcastle
,
Biochim. Biophys. Acta
1514
,
159
(
2001
).
64.
J.
Silvius
, in Lipid–Protein Interactions, edited by P. C. Jost and O. H. Griffith (Wiley, New York, 1982), pp. 239–281.
65.
D. R.
Roe
and
T. E.
Cheatham
,
J. Chem. Theory Comput.
9
,
3084
(
2013
).
66.
N.
Michaud-Agrawal
,
E. J.
Denning
,
T. B.
Woolf
, and
O.
Beckstein
,
J. Comput. Chem.
32
,
2319
(
2011
).
67.
R. J.
Gowers
, et al., in Proceedings of the 15th Python in Science Conference (
SciPy2016
, 2016), pp. 98–105.
68.
A.
Crnjar
,
F.
Comitani
,
C.
Melis
, and
C.
Molteni
,
Interface Focus
9
,
20180067
(
2019
).
69.
F.
Comitani
,
N.
Cohen
,
J.
Ashby
,
D.
Botten
,
S. C. R.
Lummis
, and
C.
Molteni
,
J. Comput. Aided Mol. Des.
28
,
35
(
2014
).
70.
F.
Comitani
,
C.
Melis
, and
C.
Molteni
,
Biochem. Soc. Trans.
43
,
151
(
2015
).
71.
F.
Comitani
,
V.
Limongelli
, and
C.
Molteni
,
J. Chem. Theory Comput.
12
,
3398
(
2016
).
72.
C.
Melis
,
S. C. R.
Lummis
, and
C.
Molteni
,
Biophys. J.
95
,
4115
(
2008
).
73.
T. J.
McCormack
,
C.
Melis
,
J.
Colon
,
E. A.
Gay
,
A.
Mike
,
R.
Karoly
,
P. W.
Lamb
,
C.
Molteni
, and
J. L.
Yakel
,
J. Physiol.
588
,
4415
(
2010
).
74.
S.
Moradi
,
A.
Nowroozi
, and
M.
Shahlaei
,
RSC Adv.
9
,
4644
(
2019
).
75.
S.
Ramadurai
,
R.
Duurkens
,
V. V.
Krasnikov
, and
B.
Poolman
,
Biophys. J.
99
,
1482
(
2010
).
76.
S. S.
Deol
,
P. J.
Bond
,
C.
Domene
, and
M. S.
Sansom
,
Biophys. J.
87
,
3737
(
2004
).
77.
S. C. R.
Lummis
,
D. L.
Beene
,
L. W.
Lee
,
H. A.
Lester
,
R. W.
Broadhurst
, and
D. A.
Dougherty
,
Nature
438
,
248
(
2005
).
78.
C.
Melis
,
G.
Bussi
,
S. C. R.
Lummis
, and
C.
Molteni
,
J. Phys. Chem. B
113
,
12148
(
2009
).
79.
N.
Calimet
,
M.
Simoes
,
J.-P.
Changeux
,
M.
Karplus
,
A.
Taly
, and
M.
Cecchini
,
Proc. Natl. Acad. Sci. U.S.A.
110
,
E3987
E3996
(
2013
).
80.
Z.-S.
Wu
,
H.
Cheng
,
Y.
Jiang
,
K.
Melcher
, and
H. E.
Xu
,
Acta Pharmacol. Sin.
36
,
895
(
2015
).
81.
I.-S.
Chen
and
Y.
Kubo
,
J. Physiol.
596
,
1833
(
2018
).
82.
G.
Klesse
,
S.
Rao
,
S. J.
Tucker
, and
M. S.
Sansom
,
J. Am. Chem. Soc.
142
,
9415
(
2020
).
83.
R. A.
Corey
,
P. J.
Stansfeld
, and
M. S.
Sansom
,
Biochem. Soc. Trans.
48
,
25
(
2019
).
84.
See supplementary material at https://doi.org/10.1116/6.0000561 for information on the RMSDs of protein sections, the MSDs and RMSFs of lipids, detailed hydrogen bonds between lipids and the M2-M3 loop and the Cys-loop, and a description of the CARC/CRAC motifs in the receptor.
85.
See http://doi.org/doi:10.18742/rdm01-613 for supporting dataset.

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