We investigate the effects of solvent specificities on the stability of the native structure (NS) of a protein on the basis of our free-energy function (FEF). We use CPB-bromodomain (CBP-BD) and apoplastocyanin (apoPC) as representatives of the protein universe and water, methanol, ethanol, and cyclohexane as solvents. The NSs of CBP-BD and apoPC consist of 66% α-helices and of 35% β-sheets and 4% α-helices, respectively. In order to assess the structural stability of a given protein immersed in each solvent, we contrast the FEF of its NS against that of a number of artificially created, misfolded decoys possessing the same amino-acid sequence but significantly different topology and α-helix and β-sheet contents. In the FEF, we compute the solvation entropy using the morphometric approach combined with the integral equation theories, and the change in electrostatic (ES) energy upon the folding is obtained by an explicit atomistic but simplified calculation. The ES energy change is represented by the break of protein-solvent hydrogen bonds (HBs), formation of protein intramolecular HBs, and recovery of solvent-solvent HBs. Protein-solvent and solvent-solvent HBs are absent in cyclohexane. We are thus able to separately evaluate the contributions to the structural stability from the entropic and energetic components. We find that for both CBP-BD and apoPC, the energetic component dominates in methanol, ethanol, and cyclohexane, with the most stable structures in these solvents sharing the same characteristics described as an association of α-helices. In particular, those in the two alcohols are identical. In water, the entropic component is as strong as or even stronger than the energetic one, with a large gain of translational, configurational entropy of water becoming crucially important so that the relative contents of α-helix and β-sheet and the content of total secondary structures are carefully selected to achieve sufficiently close packing of side chains. If the energetic component is excluded for a protein in water, the priority is given to closest side-chain packing, giving rise to the formation of a structure with very low α-helix and β-sheet contents. Our analysis, which requires minimal computational effort, can be applied to any protein immersed in any solvent and provides robust predictions that are quite consistent with the experimental observations for proteins in different solvent environments, thus paving the way toward a more detailed understanding of the folding process.

4.
C.
Tanford
,
J. Am. Chem. Soc.
84
,
4240
(
1962
).
5.
M.
Kinoshita
,
J. Chem. Phys.
128
,
024507
(
2008
).
6.
T.
Yoshidome
and
M.
Kinoshita
,
Phys. Chem. Chem. Phys.
14
,
014554
(
2012
).
8.
H.
Oshima
and
M.
Kinoshita
,
J. Chem. Phys.
142
,
145103
(
2015
).
9.
C. N.
Pace
,
S.
Treviño
,
E.
Prabhakaran
, and
J. M.
Scholts
,
Philos. Trans. R. Soc., B
359
,
1225
(
2004
).
10.
N.
Hirota
,
K.
Mizuno
, and
Y.
Goto
,
J. Mol. Biol.
275
,
365
(
1998
).
11.
T.
Hayashi
,
S.
Yasuda
,
T.
Škrbić
,
A.
Giacometti
, and
M.
Kinoshita
,
J. Chem. Phys.
147
,
125102
(
2017
).
12.
T.
Yoshidome
,
K.
Oda
,
Y.
Harano
,
R.
Roth
,
Y.
Sugita
,
M.
Ikeguchi
, and
M.
Kinoshita
,
Proteins
77
,
950
(
2009
).
13.
S.
Yasuda
,
T.
Yoshidome
,
Y.
Harano
,
R.
Roth
,
H.
Oshima
,
K.
Oda
,
Y.
Sugita
,
M.
Ikeguchi
, and
M.
Kinoshita
,
Proteins
79
,
2161
(
2011
).
14.
P.-M.
König
,
R.
Roth
, and
K. R.
Mecke
,
Phys. Rev. Lett.
93
,
160601
(
2004
).
15.
R.
Roth
,
Y.
Harano
, and
M.
Kinoshita
,
Phys. Rev. Lett.
97
,
078101
(
2006
).
16.
J.-P.
Hansen
and
L. R.
McDonald
,
Theory of Simple Liquids
, 3rd ed. (
Academic Press
,
London
,
2006
).
17.
P. G.
Kusalik
and
G. N.
Patey
,
J. Chem. Phys.
88
,
7715
(
1988
).
18.
P. G.
Kusalik
and
G. N.
Patey
,
Mol. Phys.
65
,
1105
(
1988
).
19.
M.
Kinoshita
and
D. R.
Bérard
,
J. Comput. Phys.
124
,
230
(
1996
).
20.
N. M.
Cann
and
G. N.
Patey
,
J. Chem. Phys.
106
,
8165
(
1997
).
21.
Y.
Harano
and
M.
Kinoshita
,
Biophys. J.
89
,
2701
(
2005
).
22.
S.
Yasuda
,
T.
Yoshidome
,
H.
Oshima
,
R.
Kodama
,
Y.
Harano
, and
M.
Kinoshita
,
J. Chem. Phys.
132
,
065105
(
2010
).
23.
S.
Yasuda
,
H.
Oshima
, and
M.
Kinoshita
,
J. Chem. Phys.
137
,
135103
(
2012
).
24.
T.
Yoshidome
,
M.
Kinoshita
,
S.
Hirota
,
N.
Baden
, and
M.
Terazima
,
J. Chem. Phys.
128
,
225104
(
2008
).
25.
S.
Asakura
and
F.
Oosawa
,
J. Chem. Phys.
22
,
1255
(
1954
).
26.
S.
Asakura
and
F.
Oosawa
,
J. Polym. Sci.
33
,
183
(
1958
).
27.
L.
Monchick
and
E. A.
Mason
,
J. Chem. Phys.
35
,
1676
(
1961
).
28.
W. L.
Jorgensen
,
J. Phys. Chem.
90
,
1276
(
1986
).
29.
M.
Kinoshita
and
M.
Harada
,
Mol. Phys.
74
,
443
(
1991
).
30.
N. P.
Funnell
,
M. T.
Dove
,
A. L.
Goodwin
,
S.
Parsons
, and
M. G.
Tucker
,
J. Phys.: Condens. Matter
25
,
454204
(
2013
).
31.
T.
Imai
,
Y.
Harano
,
M.
Kinoshita
,
A.
Kovalenko
, and
F.
Hirata
,
J. Chem. Phys.
125
,
024911
(
2006
).
33.
M. L.
Connolly
,
J. Am. Chem. Soc.
107
,
1118
(
1985
).
34.
A. D.
MacKerell
, Jr.
,
D.
Bashford
,
M.
Bellott
,
R. L.
Dunbrack
, Jr.
,
J. D.
Evanseck
,
M. J.
Field
,
S.
Fischer
,
J.
Gao
,
H.
Guo
,
S.
Ha
,
D.
Joseph-McCarthy
,
L.
Kuchnir
,
K.
Kuczera
,
F. T. K.
Lau
,
C.
Mattos
,
S.
Michnick
,
T.
Ngo
,
D. T.
Nguyen
,
B.
Prodhom
,
W. E.
Reiher
 III
,
B.
Roux
,
M.
Schlenkrich
,
J. C.
Smith
,
R.
Stote
,
J.
Straub
,
M.
Watanabe
,
J.
Wiov́rkiewicz-Kuczera
,
D.
Yin
, and
M.
Karplus
,
J. Phys. Chem. B
102
,
3586
(
1998
).
35.
M.
Ikeguchi
and
J.
Doi
,
J. Chem. Phys.
103
,
5011
(
1995
).
36.
M.
Kinoshita
,
J. Chem. Phys.
116
,
3493
(
2002
).
37.
C. N.
Likos
,
K. R.
Mecke
, and
H.
Wagner
,
J. Chem. Phys.
102
,
9350
(
1995
).
38.
M.
Kinoshita
and
T.
Hayashi
,
Phys. Chem. Chem. Phys.
19
,
25891
(
2017
).
39.
I. K.
McDonald
and
J. M.
Thornton
,
J. Mol. Biol.
238
,
777
(
1994
).
40.
J. B. O.
Mitchell
and
S. L.
Price
,
Chem. Phys. Lett.
180
,
517
(
1991
).
41.
M.
Kinoshita
,
Y.
Okamoto
, and
F.
Hirata
,
J. Am. Chem. Soc.
122
,
2773
(
2000
).
42.
J. S.
Perkyns
and
B. M.
Pettitt
,
J. Chem. Phys.
97
,
7656
(
1992
).
43.
B. M.
Pettit
and
P. J.
Rossky
,
J. Chem. Phys.
77
,
1451
(
1982
).
44.
H. J. C.
Berendsen
,
J. R.
Grigera
, and
T. P.
Straatsma
,
J. Phys. Chem.
91
,
6269
(
1987
).
45.
S.
Mujtaba
,
Y.
He
,
L.
Zeng
,
S.
Yan
,
O.
Plotnikova
,
R.
Sachchidanand Sanchez
,
N. J.
Zeleznik-Le
,
Z.
Ronai
, and
M.-M.
Zhou
,
Mol. Cell
13
,
251
(
2004
).
46.
T. P. J.
Garrett
,
D. J.
Clingeleffer
,
J. M.
Guss
,
S. J.
Rogers
, and
H. C.
Freeman
,
J. Biol. Chem.
259
,
2822
(
1984
).
47.
W.
Kabsch
and
C.
Sander
,
Biopolymers
22
,
2577
(
1983
).
48.
H.
Deng
,
Y.
Jia
, and
Y.
Zhang
,
Bioinformatics
32
,
378
(
2016
).
49.
V. B.
Chen
,
W. B.
Arendall
 III
,
J. J.
Headd
,
D. A.
Keedy
,
R. M.
Immormino
,
G. J.
Kapral
,
L. W.
Murray
,
J. S.
Richardson
, and
D. C.
Richardson
,
Acta Crystallogr., Sect. D: Biol. Crystallogr.
66
,
12
(
2010
), http://kinemage.biochem.duke.edu/databases/top8000.php.
50.
T.
Skrbic
,
A.
Badasyan
,
T.
Hoang
,
R.
Podgornik
, and
A.
Giacometti
,
Soft Matter
12
,
4783
(
2016
).
51.
T.
Skrbic
,
T.
Hoang
, and
A.
Giacometti
,
J. Chem. Phys.
145
,
084904
(
2016
).
52.
P.
Rotkiewicz
and
J.
Skolnick
,
J. Comput. Chem.
29
,
1460
(
2008
).
53.
D.
van der Spoel
,
E.
Lindahl
,
B.
Hess
,
G.
Groenhof
,
A. E.
Mark
, and
H. J. C.
Berendsen
,
J. Comput. Chem.
26
,
1701
(
2005
).
54.
B. R.
Brooks
,
R. E.
Bruccoleri
,
B. D.
Olafson
,
D. J.
States
,
S.
Swaminathan
, and
M.
Karplus
,
J. Comput. Chem.
4
,
187
(
1983
).
55.
M.
Feig
,
J.
Karanicolas
, and
C. L.
Brooks
 III
,
J. Mol. Graphics Modell.
22
,
377
(
2004
).
56.
A. D.
Mackerell
, Jr.
,
M.
Feig
, and
C. L.
Brooks
 III
,
J. Comput. Chem.
25
,
1400
(
2004
).
57.
M. S.
Lee
,
M.
Feig
,
F. R.
Salsbury
, Jr.
, and
C. L.
Brooks
 III
,
J. Comput. Chem.
24
,
1348
(
2003
).
58.
J.
Chocholoušovav́
and
M.
Feig
,
J. Comput. Chem.
27
,
719
(
2006
).
59.
K.
Griebenow
and
A. M.
Klibanov
,
J. Am. Chem. Soc.
118
,
11695
(
1996
).
61.
T.
Lazaridis
and
M. E.
Paulaitis
,
J. Phys. Chem.
96
,
3847
(
1992
).
62.
H. S.
Ashbaugh
and
M. E.
Paulaitis
,
J. Phys. Chem.
100
,
1900
(
1996
).
63.
T.
Yoshidome
,
Y.
Harano
, and
M.
Kinoshita
,
Phys. Rev. E
79
,
011912
(
2009
).
64.
Y.
Karino
and
N.
Matubayasi
,
J. Chem. Phys.
134
,
041105
(
2011
).
65.
F.
Kamo
,
R.
Ishizuka
, and
N.
Matubayasi
,
Protein Sci.
25
,
56
(
2016
).
66.
Y.
Yamamori
,
R.
Ishizuka
,
Y.
Karino
,
S.
Sakuraba
, and
N.
Matubayasi
,
J. Chem. Phys.
144
,
085102
(
2016
).
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