C99, a naturally occurring peptide, is a precursor of the amyloid β-peptide (Aβ) and plays an important role in the so-called amyloidogenic pathway of degradation of amyloid precursor protein. While the effect of C99’s dimerization is not clearly determined, it has been hypothesized that the dimerization protects C99 from being cleaved further. Cholesterol (CHOL) is known to interact with C99 and its presence in high concentrations has been linked to an increase in the production of Aβ; however, to what extent this is correlated, and how, has not yet been determined. In this study, we systematically examine the effect of increasing cholesterol concentration on the homodimerization propensity of C99, combining unbiased atomistic molecular dynamics simulations with biased simulations using a coarse grained resolution. Through the use of umbrella sampling, we show how the presence of high levels of CHOL destabilizes the interaction between two C99 monomers. The interaction pattern between the two C99s has shifted several residues, from the N-terminal end of the transmembrane region toward the corresponding C-terminal in the presence of CHOL. The umbrella sampling shows that the presence of high levels of CHOL led to a decrease of the disassociation energy by approximately 3 kJ/mol. In conclusion, this suggests that increasing CHOL destabilizes the interaction between the two C99 monomers, which may possibly cause an increase in the production of Aβ42.

1.
P. J.
Barrett
,
Y.
Song
,
W. D.
Van Horn
,
E. J.
Hustedt
,
J. M.
Schafer
,
A.
Hadziselimovic
,
A. J.
Beel
, and
C. R.
Sanders
,
Science
336
,
1168
(
2012
).
2.
A.
Panahi
,
A.
Bandara
,
G. A.
Pantelopulos
,
L.
Dominguez
, and
J. E.
Straub
,
J. Phys. Chem. Lett.
7
,
3535
(
2016
).
4.
Y.-M.
Kuo
,
M. R.
Emmerling
,
C.
Vigo-Pelfrey
,
T. C.
Kasunic
,
J. B.
Kirkpatrick
,
G. H.
Murdoch
,
M. J.
Ball
, and
A. E.
Roher
,
J. Biol. Chem.
271
,
4077
(
1996
).
6.
G. A.
Pantelopulos
,
J. E.
Straub
,
D.
Thirumalai
, and
Y.
Sugita
,
Biochim. Biophys. Acta Biomembr.
1860
,
1698
(
2018
).
7.
V.
Wilquet
and
B. D.
Strooper
,
Curr. Opin. Neurobiol.
14
,
582
(
2004
).
8.
V. W.
Chow
,
M. P.
Mattson
,
P. C.
Wong
, and
M.
Gleichmann
,
NeuroMol. Med.
12
,
1
(
2010
).
9.
M. O.
Grimm
,
H. S.
Grimm
,
I.
Tomic
,
K.
Beyreuther
,
T.
Hartmann
, and
C.
Bergmann
,
J. Biol. Chem.
283
,
11302
(
2008
).
10.
Y.
Song
,
E. J.
Hustedt
,
S.
Brandon
, and
C. R.
Sanders
,
Biochemistry
52
,
5051
(
2013
).
11.
L.-M.
Munter
 et al,
EMBO J.
26
,
1702
(
2007
).
12.
Y.
Yan
,
T.-H.
Xu
,
K. G.
Harikumar
,
L. J.
Miller
,
K.
Melcher
, and
H. E.
Xu
,
J. Biol. Chem.
292
,
15826
(
2017
).
13.
E.
Winkler
,
A.
Julius
,
H.
Steiner
, and
D.
Langosch
,
Biochemistry
54
,
6149
(
2015
).
14.
S.
Eggert
,
B.
Midthune
,
B.
Cottrell
, and
E. H.
Koo
,
J. Biol. Chem.
284
,
28943
(
2009
).
15.
L.
Dominguez
,
L.
Foster
,
J. E.
Straub
, and
D.
Thirumalai
,
Proc. Natl. Acad. Sci. U.S.A.
113
,
E5281
(
2016
).
16.
C.-D.
Li
,
M.
Junaid
,
H.
Chen
,
A.
Ali
, and
D.-Q.
Wei
,
J. Chem. Inf. Model.
59
,
339
(
2019
).
17.
L.
Dominguez
,
L.
Foster
,
S. C.
Meredith
,
J. E.
Straub
, and
D.
Thirumalai
,
J. Am. Chem. Soc.
136
,
9619
(
2014
).
18.
M. A.
Martí-Renom
,
A. C.
Stuart
,
A.
Fiser
,
R.
Sánchez
,
F.
Melo
, and
A.
Sali
,
Annu. Rev. Biophys. Biomol. Struct.
29
,
291
(
2000
).
19.
A.
Fiser
,
R. K.
Do
, and
A.
Sali
,
Protein Sci.
9
,
1753
(
2000
).
20.
B.
Webb
and
A.
Sali
,
Curr. Protoc. Bioinf.
54
,
5.6.1
(
2016
).
21.
A.
Sali
and
T. L.
Blundell
,
J. Mol. Biol.
234
,
779
(
1993
).
22.
O.
Crescenzi
,
S.
Tomaselli
,
R.
Guerrini
,
S.
Salvadori
,
A. M.
D’Ursi
,
P. A.
Temussi
, and
D.
Picone
,
Eur. J. Biochem.
269
,
5642
(
2002
).
23.
P. J.
Barrett
,
Y.
Song
,
W. D.
Van Horn
,
E. J.
Hustedt
,
J. M.
Schafer
,
A.
Hadziselimovic
,
A. J.
Beel
, and
C. R.
Sanders
,
Science
336
,
1168
(
2012
).
24.
K. D.
Nadezhdin
,
O. V.
Bocharova
,
E. V.
Bocharov
, and
A. S.
Arseniev
,
FEBS Lett.
586
,
1687
(
2012
).
25.
J.
Radzimanowski
,
B.
Simon
,
M.
Sattler
,
K.
Beyreuther
,
I.
Sinning
, and
K.
Wild
,
EMBO Rep.
9
,
1134
(
2008
).
26.
H. M.
Berman
,
J.
Westbrook
,
Z.
Feng
,
G.
Gilliland
,
T. N.
Bhat
,
H.
Weissig
,
I. N.
Shindyalov
, and
P. E.
Bourne
,
Nucleic Acids Res.
28
,
235
(
2000
).
27.
See Schrödinger, LLC, New York, NY, 2017.
28.
M. H. M.
Olsson
,
C. R.
Søndergaard
,
M.
Rostkowski
, and
J. H.
Jensen
,
J. Chem. Theory Comput.
7
,
525
(
2011
).
29.
C. R.
Søndergaard
,
M. H. M.
Olsson
,
M.
Rostkowski
, and
J. H.
Jensen
,
J. Chem. Theory Comput.
7
,
2284
(
2011
).
30.
D. H.
de Jong
,
G.
Singh
,
W. F. D.
Bennett
,
C.
Arnarez
,
T. A.
Wassenaar
,
L. V.
Schäfer
,
X.
Periole
,
D. P.
Tieleman
, and
S. J.
Marrink
,
J. Chem. Theory Comput.
9
,
687
(
2013
).
31.
T. A.
Wassenaar
,
H. I.
Ingólfsson
,
R. A.
Böckmann
,
D. P.
Tieleman
, and
S. J.
Marrink
,
J. Chem. Theory Comput.
11
,
2144
(
2015
).
32.
S. J.
Marrink
,
A. H.
de Vries
, and
A. E.
Mark
,
J. Phys. Chem. B
108
,
750
(
2004
).
33.
T. C.
Beutler
,
A. E.
Mark
,
R. C.
van Schaik
,
P. R.
Gerber
, and
W. F.
van Gunsteren
,
Chem. Phys. Lett.
222
,
529
(
1994
).
34.
G.
Bussi
,
D.
Donadio
, and
M.
Parrinello
,
J. Chem. Phys.
126
,
014101
(
2007
).
35.
H. J. C.
Berendsen
,
J. P. M.
Postma
,
W. F.
van Gunsteren
,
A.
DiNola
, and
J. R.
Haak
,
J. Chem. Phys.
81
,
3684
(
1984
).
36.
T. A.
Wassenaar
,
K.
Pluhackova
,
R. A.
Böckmann
,
S. J.
Marrink
, and
D. P.
Tieleman
,
J. Chem. Theory Comput.
10
,
676
(
2014
).
37.
J.
Huang
,
S.
Rauscher
,
G.
Nawrocki
,
T.
Ran
,
M.
Feig
,
B. L.
de Groot
,
H.
Grubmüller
, and
A. D.
MacKerell
,
Jr.
,
Nat. Methods
14
,
71
(
2016
).
38.
S.
Jo
,
T.
Kim
,
V. G.
Iyer
, and
W.
Im
,
J. Comput. Chem.
29
,
1859
(
2008
).
39.
X.
Daura
,
K.
Gademann
,
B.
Jaun
,
D.
Seebach
,
W. F.
van Gunsteren
, and
A. E.
Mark
,
Angew. Chem. Int. Ed.
38
,
236
(
1999
).
40.
W.
Humphrey
,
A.
Dalke
, and
K.
Schulten
,
J. Mol. Graph.
14
,
33
(
1996
).
41.
G. A.
Tribello
,
M.
Bonomi
,
D.
Branduardi
,
C.
Camilloni
, and
G.
Bussi
,
Comput. Phys. Commun.
185
,
604
(
2014
).
42.
M. K.
Scherer
,
B.
Trendelkamp-Schroer
,
F.
Paul
,
G.
Pérez-Hernández
,
M.
Hoffmann
,
N.
Plattner
,
C.
Wehmeyer
,
J.-H.
Prinz
, and
F.
Noé
,
J. Chem. Theory Comput.
11
,
5525
(
2015
).
43.
B. M. H.
Bruininks
,
P. C. T.
Souza
, and
S. J.
Marrink
, in
Methods in Molecular Biology
, edited by
M.
Bonomi
and
C.
Camilloni
(
Springer
,
New York
,
2019
), Vol. 2022, pp.
105
127
.
45.
U.
Igbavboa
,
N. A.
Avdulov
,
F.
Schroeder
, and
W. G.
Wood
,
J. Neurochem.
66
,
1717
(
1996
).
46.
See supplementary material at https://www.scitation.org/doi/suppl/10.1116/6.0000985 for the sequence used to model C99.

Supplementary Material

You do not currently have access to this content.