A method for evaluating binding free energy differences of protein-protein complex structures generated by protein docking was recently developed by some of us. The method, termed evERdock, combined short (2 ns) molecular dynamics (MD) simulations in explicit water and solution theory in the energy representation (ER) and succeeded in selecting the near-native complex structures from a set of decoys. In the current work, we performed longer (up to 100 ns) MD simulations before employing ER analysis in order to further refine the structures of the decoy set with improved binding free energies. Moreover, we estimated the binding free energies for each complex structure based on an average value from five individual MD snapshots. After MD simulations, all decoys exhibit a decrease in binding free energy, suggesting that proper equilibration in explicit solvent resulted in more favourably bound complexes. During the MD simulations, non-native structures tend to become unstable and in some cases dissociate, while near-native structures maintain a stable interface. The energies after the MD simulations show an improved correlation between similarity criteria (such as interface root-mean-square distance) to the native (crystal) structure and the binding free energy. In addition, calculated binding free energies show sensitivity to the number of contacts, which was demonstrated to reflect the relative stability of structures at earlier stages of the MD simulation. We therefore conclude that the additional equilibration step along with the use of multiple conformations can make the evERdock scheme more versatile under low computational cost.

1.
O.
Keskin
,
A.
Gursoy
,
B.
Ma
, and
R.
Nussinov
,
Chem. Rev.
108
,
1225
(
2008
).
2.
M. F.
Lensink
and
S. J.
Wodak
,
Proteins: Struct., Funct., Bioinf.
81
,
2082
(
2013
).
3.
G.
Sudha
,
R.
Nussinov
, and
N.
Srinivasan
,
Prog. Biophys. Mol. Biol.
116
,
141
(
2014
).
4.
J.
Janin
and
B.
Séraphin
,
Curr. Opin. Struct. Biol.
13
,
383
(
2003
).
5.
O.
Keskin
,
C.-J.
Tsai
,
H.
Wolfson
, and
R.
Nussinov
,
Protein Sci.
13
,
1043
(
2004
).
6.
B. A.
Shoemaker
and
A. R.
Panchenko
,
PLoS Comput. Biol.
3
,
e42
(
2007
).
7.
I. H.
Moal
,
R.
Agius
, and
P. A.
Bates
,
Bioinformatics
27
,
3002
(
2011
).
8.
R.
Moretti
,
S. J.
Fleishman
,
R.
Agius
,
M.
Torchala
,
P. A.
Bates
,
P. L.
Kastritis
,
J. P.
Rodrigues
,
M.
Trellet
,
A. M.
Bonvin
,
M.
Cui
 et al,
Proteins: Struct., Funct., Bioinf.
81
,
1980
(
2013
).
9.
T. L.
Blundell
,
H.
Jhoti
, and
C.
Abell
,
Nat. Rev. Drug Discovery
1
,
45
(
2002
).
10.
E. R.
Zuiderweg
,
Biochemistry
41
,
1
(
2002
).
11.
L. C.
Xue
,
D.
Dobbs
,
A. M.
Bonvin
, and
V.
Honavar
,
FEBS Lett.
589
,
3516
(
2015
).
12.
M. F.
Lensink
,
S.
Velankar
, and
S. J.
Wodak
,
Proteins: Struct., Funct., Bioinf.
85
,
359
(
2017
).
13.
I.
Halperin
,
B.
Ma
,
H.
Wolfson
, and
R.
Nussinov
,
Proteins: Struct., Funct., Bioinf.
47
,
409
(
2002
).
14.
P. L.
Kastritis
and
A. M.
Bonvin
,
Curr. Opin. Struct. Biol.
23
,
868
(
2013
).
15.
P. L.
Kastritis
and
A. M.
Bonvin
,
J. Proteome Res.
9
,
2216
(
2010
).
16.
T.
Hou
,
J.
Wang
,
Y.
Li
, and
W.
Wang
,
J. Chem. Inf. Model.
51
,
69
(
2010
).
17.
J. C.
Gumbart
,
B.
Roux
, and
C.
Chipot
,
J. Chem. Theory Comput.
9
,
3789
(
2013
).
18.
F.
Chen
,
H.
Liu
,
H.
Sun
,
P.
Pan
,
Y.
Li
,
D.
Li
, and
T.
Hou
,
Phys. Chem. Chem. Phys.
18
,
22129
(
2016
).
19.
M.
Aldeghi
,
M. J.
Bodkin
,
S.
Knapp
, and
P. C.
Biggin
,
J. Chem. Inf. Model.
57
,
2203
(
2017
).
20.
J. S.
Patel
and
F. M.
Ytreberg
,
J. Chem. Theory Comput.
14
,
991
(
2018
).
21.
P.
Kollman
,
Chem. Rev.
93
,
2395
(
1993
).
22.
S.
Genheden
and
U.
Ryde
,
Expert Opin. Drug Discov
10
,
449
(
2015
).
23.
D.
Shivakumar
,
Y.
Deng
, and
B.
Roux
,
J. Chem. Theory Comput.
5
,
919
(
2009
).
24.
M. S.
Lee
and
M. A.
Olson
,
Biophys. J.
90
,
864
(
2006
).
25.
P. A.
Greenidge
,
C.
Kramer
,
J.-C.
Mozziconacci
, and
R. M.
Wolf
,
J. Chem. Inf. Model.
53
,
201
(
2012
).
26.
K.
Takemura
,
H.
Guo
,
S.
Sakuraba
,
N.
Matubayasi
, and
A.
Kitao
,
J. Chem. Phys.
137
,
215105
(
2012
).
27.
K.
Takemura
,
N.
Matubayasi
, and
A.
Kitao
,
J. Chem. Phys.
148
,
105101
(
2018
).
28.
N.
Matubayasi
and
M.
Nakahara
,
J. Chem. Phys.
117
,
3605
(
2002
).
29.
S.
Sakuraba
and
N.
Matubayasi
,
J. Comput. Chem.
35
,
1592
(
2014
).
30.
N.
Matubayasi
,
Curr. Opin. Struct. Biol.
43
,
45
(
2017
).
31.
H.
Fan
and
A. E.
Mark
,
Protein Sci.
13
,
211
(
2004
).
32.
J.
Chen
and
C. L.
Brooks
,
Proteins: Struct., Funct., Bioinf.
67
,
922
(
2007
).
33.
T.
Hou
,
J.
Wang
,
Y.
Li
, and
W.
Wang
,
J. Comput. Chem.
32
,
866
(
2011
).
34.
K.
Liu
and
H.
Kokubo
,
J. Chem. Inf. Model.
57
,
2514
(
2017
).
35.
P.
Jeřábek
,
J.
Florián
,
M.
Stiborová
, and
V.
Martínek
,
Biochemistry
53
,
6695
(
2014
).
36.
E. A.
Proctor
,
S.
Yin
,
A.
Tropsha
, and
N. V.
Dokholyan
,
Biophys. J.
102
,
144
(
2012
).
37.
M.
Masetti
,
A.
Cavalli
,
M.
Recanatini
, and
F. L.
Gervasio
,
J. Phys. Chem. B
113
,
4807
(
2009
).
38.
J.
Sevcik
,
L.
Urbanikova
,
Z.
Dauter
, and
K. S.
Wilson
,
Acta Crystallogr., Sect. D: Biol. Crystallogr.
54
,
954
(
1998
).
39.
W.
Bode
,
H. J.
Greyling
,
R.
Huber
,
J.
Otlewski
, and
T.
Wilusz
,
FEBS Lett.
242
,
285
(
1989
).
40.
J.
Mintseris
,
K.
Wiehe
,
B.
Pierce
,
R.
Anderson
,
R.
Chen
,
J.
Janin
, and
Z.
Weng
,
Proteins: Struct., Funct., Bioinf.
60
,
214
(
2005
).
41.
R.
Chen
and
Z.
Weng
,
Proteins: Struct., Funct., Bioinf.
47
,
281
(
2002
).
42.
B. G.
Pierce
,
Y.
Hourai
, and
Z.
Weng
,
PLoS One
6
,
e24657
(
2011
).
43.
W.
Humphrey
,
A.
Dalke
, and
K.
Schulten
,
J. Mol. Graphics
14
,
33
(
1996
).
44.
A.
Leaver-Fay
,
M.
Tyka
,
S. M.
Lewis
,
O. F.
Lange
,
J.
Thompson
,
R.
Jacak
,
K. W.
Kaufman
,
P. D.
Renfrew
,
C. A.
Smith
,
W.
Sheffer
 et al,
Methods Enzymol.
487
,
545
(
2011
).
45.
J. C.
Phillips
,
R.
Braun
,
W.
Wang
,
J.
Gumbart
,
E.
Tajkhorshid
,
E.
Villa
,
C.
Chipot
,
R. D.
Skeel
,
L.
Kale
, and
K.
Schulten
,
J. Comput. Chem.
26
,
1781
(
2005
).
46.
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
(
2017
).
47.
F.
Figueirido
,
G. S.
Del Buono
, and
R. M.
Levy
,
J. Chem. Phys.
103
,
6133
(
1995
).
48.
Y.
Karino
and
N.
Matubayasi
,
J. Chem. Phys.
134
,
041105
(
2011
).
49.
C.-J.
Tsai
,
S. L.
Lin
,
H. J.
Wolfson
, and
R.
Nussinov
,
Protein Sci.
6
,
53
(
1997
).
50.
L.
Young
,
R. L.
Jernigan
, and
D. G.
Covell
,
Protein Sci.
3
,
717
(
1994
).
51.
J.
Kyte
,
Biophys. Chem.
100
,
193
(
2002
).
52.
J. D.
Dunitz
,
Chem. Biol.
2
,
709
(
1995
).
53.
J. P.
Rodrigues
,
M.
Trellet
,
C.
Schmitz
,
P.
Kastritis
,
E.
Karaca
,
A. S.
Melquiond
, and
A. M.
Bonvin
,
Proteins: Struct., Funct., Bioinf.
80
,
1810
(
2012
).
54.
S.
Wallin
,
J.
Farwer
, and
U.
Bastolla
,
Proteins: Struct., Funct., Bioinf.
50
,
144
(
2003
).
55.
A. D.
Van Dijk
and
A. M.
Bonvin
,
Bioinformatics
22
,
2340
(
2006
).
56.
P. L.
Kastritis
and
A. M.
Bonvin
,
J. R. Soc., Interface
10
,
20120835
(
2013
).
57.
I.
Maffucci
and
A.
Contini
,
J. Chem. Inf. Model.
56
,
1692
(
2016
).
58.
F.
Rodier
,
R. P.
Bahadur
,
P.
Chakrabarti
, and
J.
Janin
,
Proteins: Struct., Funct., Bioinf.
60
,
36
(
2005
).
59.
N. A.
Meenan
,
A.
Sharma
,
S. J.
Fleishman
,
C. J.
MacDonald
,
B.
Morel
,
R.
Boetzel
,
G. R.
Moore
,
D.
Baker
, and
C.
Kleanthous
,
Proc. Natl. Acad. Sci. U. S. A.
107
,
10080
(
2010
).
60.
D.
Cui
,
B. W.
Zhang
,
N.
Matubayasi
, and
R. M.
Levy
,
J. Chem. Theory Comput.
14
,
512
(
2018
).
61.
M. F.
Lensink
,
I. H.
Moal
,
P. A.
Bates
,
P. L.
Kastritis
,
A. S.
Melquiond
,
E.
Karaca
,
C.
Schmitz
,
M.
van Dijk
,
A. M.
Bonvin
,
M.
Eisenstein
 et al,
Proteins: Struct., Funct., Bioinf.
82
,
620
(
2014
).
62.
S.
Omori
and
A.
Kitao
,
Proteins: Struct., Funct., Bioinf.
81
,
1005
(
2013
).

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