The partitioning of small molecules in cell membranes—a key parameter for pharmaceutical applications—typically relies on experimentally available bulk partitioning coefficients. Computer simulations provide a structural resolution of the insertion thermodynamics via the potential of mean force but require significant sampling at the atomistic level. Here, we introduce high-throughput coarse-grained molecular dynamics simulations to screen thermodynamic properties. This application of physics-based models in a large-scale study of small molecules establishes linear relationships between partitioning coefficients and key features of the potential of mean force. This allows us to predict the structure of the insertion from bulk experimental measurements for more than 400 000 compounds. The potential of mean force hereby becomes an easily accessible quantity—already recognized for its high predictability of certain properties, e.g., passive permeation. Further, we demonstrate how coarse graining helps reduce the size of chemical space, enabling a hierarchical approach to screening small molecules.

1.
D.
Lopes
,
S.
Jakobtorweihen
,
C.
Nunes
,
B.
Sarmento
, and
S.
Reis
,
Prog. Lipid Res.
65
,
24
(
2016
).
2.
W.
Shinoda
,
Biochim. Biophys. Acta, Biomembr.
1858
,
2254
(
2016
).
3.
S. S. F.
Leung
,
D.
Sindhikara
, and
M. P.
Jacobson
,
J. Chem. Inf. Model.
56
,
924
(
2016
).
4.
R. B. V.
Breemen
and
Y.
Li
,
Expert Opin. Drug Metab. Toxicol.
1
,
175
(
2005
).
5.
J. L.
MacCallum
,
W. D.
Bennett
, and
D. P.
Tieleman
,
Biophys. J.
94
,
3393
(
2008
).
6.
T. S.
Carpenter
,
D. A.
Kirshner
,
E. Y.
Lau
,
S. E.
Wong
,
J. P.
Nilmeier
, and
F. C.
Lightstone
,
Biophys. J.
107
,
630
(
2014
).
7.
C. T.
Lee
,
J.
Comer
,
N. L.
Conner Herndon
,
A.
Pavlova
,
R. V.
Swift
,
C.
Tung
,
C. N.
Rowley
,
R. E.
Amaro
,
C.
Chipot
,
Y.
Wang
, and
J. C.
Gumbart
,
J. Chem. Inf. Model.
56
,
721
(
2016
).
8.
B. J.
Bennion
,
N. A.
Be
,
M. W.
McNerney
,
V.
Lao
,
E. M.
Carlson
,
C. A.
Valdez
,
M. A.
Malfatti
,
H. A.
Enright
,
T. H.
Nguyen
,
F. C.
Lightstone
, and
T. S.
Carpenter
,
J. Phys. Chem. B
121
,
5228
(
2017
).
9.
S.
Jakobtorweihen
,
A. C.
Zuniga
,
T.
Ingram
,
T.
Gerlach
,
F. J.
Keil
, and
I.
Smirnova
,
J. Chem. Phys.
141
,
045102
(
2014
).
10.
C.
Neale
,
W. D.
Bennett
,
D. P.
Tieleman
, and
R.
Pomès
,
J. Chem. Theory Comput.
7
,
4175
(
2011
).
11.
G. A.
Voth
,
Coarse-Graining of Condensed Phase and Biomolecular Systems
(
CRC Press
,
Boca Raton, FL
,
2008
).
12.
W. G.
Noid
,
J. Chem. Phys.
139
,
090901
(
2013
).
13.
X.
Periole
and
S.-J.
Marrink
, “
The Martini coarse-grained force field
,” in
Biomolecular Simulations: Methods and Protocols
(
Humana Press
,
2013
), pp.
533
565
.
14.
S. J.
Marrink
and
D. P.
Tieleman
,
Chem. Soc. Rev.
42
,
6801
(
2013
).
15.
B.
Hess
,
C.
Kutzner
,
D.
Van Der Spoel
, and
E.
Lindahl
,
J. Chem. Theory Comput.
4
,
435
447
(
2008
).
16.
S. J.
Marrink
,
A. H.
de Vries
, and
A. E.
Mark
,
J. Phys. Chem. B
108
,
750
(
2004
).
17.
S. J.
Marrink
,
H. J.
Risselada
,
S.
Yefimov
,
D. P.
Tieleman
, and
A. H.
de Vries
,
J. Phys. Chem. B
111
,
7812
(
2007
).
18.
L.
Monticelli
,
S. K.
Kandasamy
,
X.
Periole
,
R. G.
Larson
,
D. P.
Tieleman
, and
S.-J.
Marrink
,
J. Chem. Theory Comput.
4
,
819
(
2008
).
19.
D. H.
De Jong
,
G.
Singh
,
W. D.
Bennett
,
C.
Arnarez
,
T. A.
Wassenaar
,
L. V.
Schafer
,
X.
Periole
,
D. P.
Tieleman
, and
S. J.
Marrink
,
J. Chem. Theory Comput.
9
,
687
(
2013
).
20.
D. H.
De Jong
,
S.
Baoukina
,
H. I.
Ingólfsson
, and
S. J.
Marrink
,
Comput. Phys. Commun.
199
,
1
(
2016
).
21.
M.
Parrinello
and
A.
Rahman
,
J. Appl. Phys.
52
,
7182
(
1981
).
22.
G.
Bussi
,
D.
Donadio
, and
M.
Parrinello
,
J. Chem. Phys.
126
,
014101
(
2007
).
23.
T. A.
Wassenaar
,
H. I.
Ingólfsson
,
R. A.
Böckmann
,
D. P.
Tieleman
, and
S. J.
Marrink
,
J. Chem. Theory Comput.
11
,
2144
(
2015
).
24.
G. M.
Torrie
and
J. P.
Valleau
,
J. Comput. Phys.
23
,
187
(
1977
).
25.
T.
Bereau
,
Z.-J.
Wang
, and
M.
Deserno
,
J. Chem. Phys.
140
,
115101
(
2014
).
26.
S.
Kumar
,
J. M.
Rosenberg
,
D.
Bouzida
,
R. H.
Swendsen
, and
P. A.
Kollman
,
J. Comput. Chem.
13
,
1011
(
1992
).
27.
T.
Bereau
and
R. H.
Swendsen
,
J. Comput. Phys.
228
,
6119
(
2009
).
28.
J. S.
Hub
,
B. L.
De Groot
, and
D.
Van Der Spoel
,
J. Chem. Theory Comput.
6
,
3713
(
2010
).
29.
C. Z.
Mooney
,
R. D.
Duval
, and
R.
Duvall
,
Bootstrapping: A Nonparametric Approach to Statistical Inference
(
Sage
,
1993
), pp.
94
95
.
30.
T.
Bereau
and
K.
Kremer
,
J. Chem. Theory Comput.
11
,
2783
(
2015
).
31.
C.
Chipot
and
A.
Pohorille
,
Free Energy Calculations
(
Springer
,
2007
).
32.
A.
Nikolic
,
S.
Baud
,
S.
Rauscher
, and
R.
Pomès
,
Proteins: Struct., Funct., Bioinf.
79
,
1
(
2011
).
33.
M. R.
Shirts
and
J. D.
Chodera
,
J. Chem. Phys.
129
,
124105
(
2008
).
34.
C. H.
Bennett
,
J. Comput. Phys.
22
,
245
(
1976
).
35.
T.
Fink
,
H.
Bruggesser
, and
J.-L.
Reymond
,
Angew. Chem., Int. Ed.
44
,
1504
(
2005
).
36.
T.
Fink
and
J.-l.
Reymond
,
J. Chem. Inf. Model.
47
,
342
(
2007
).
37.
I. V.
Tetko
,
V. Y.
Tanchuk
, and
a. E.
Villa
,
J. Chem. Inf. Comput. Sci.
41
,
1407
(
2001
).
38.
I. V.
Tetko
and
V. Y.
Tanchuk
,
J. Chem. Inf. Comput. Sci.
42
,
1136
(
2002
).
39.
A.
Toulmin
,
J. M.
Wood
, and
P. W.
Kenny
,
J. Med. Chem.
51
,
3720
(
2008
).
40.
J. M.
Diamond
and
Y.
Katz
,
J. Membrane Biol.
17
,
121
(
1974
).
41.
S.-J.
Marrink
and
H. J.
Berendsen
,
J. Phys. Chem.
98
,
4155
(
1994
).
42.
R. V.
Swift
and
R. E.
Amaro
,
Chem. Biol. Drug Des.
81
,
61
(
2013
).

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